A Review on Innovative Strategies Towards Sustainable Drug Waste Management Through Algae-Based Systems

Abstract

Drug removal from urban wastewater (UW) is a topic of growing interest. The new European Directive addresses this problem by introducing quaternary treatment by 2045, as part of the “Zero Pollution” plan from a One Health perspective. In this context, the role of microalgae remains very promising in achieving clean and safe effluents, although its cost–benefit ratio needs to be carefully evaluated. The purpose of this review is to disclose the latest approaches to drug removal and energy recovery from UWs adopting different algae (Chlorella spp., Galdieria spp., and Scenedesmus spp.), to provide a detailed background for further research towards the development of new effective strategies on UW remediation while producing clean energy. We examined the most recent studies, considering most drugs found in wastewater, their management, as well as strategies used to recover energy while being mindful of a circular economy. There is growing interest in algae-based systems. The latest findings on algae–bacteria consortia show that it could be a better alternative to suspended biomass and represent a way to manage drug waste. This finding suggests that large-scale experiments should be conducted to confirm the potential benefits of such waste treatments.

1. Introduction

Emerging contaminants (ECs) represent a strong element of scientific interest because of the minimal amount of information about their behavior once released into the environment [1,2]. Drugs surely belong to the EC category; their use increases year by year because of recent public health threats faced by humans and their current lifestyles [3]. Antibiotic resistance (AMR) is a growing threat to humanity and has a negative impact on public health and the economy. According to the latest available data provided by the World Health Organization (WHO) and World Bank Group in 2019, AMR accounted for more than 1.20 million deaths globally and was associated with 4.95 million deaths [4,5]. In Europe, according to the WHO, AMR causes approximately 133,000 direct deaths annually and contributes to 541,000 indirect deaths, a number comparable to deaths from tuberculosis, malaria, and HIV/AIDS combined. It is estimated that AMR costs about EUR 11.7 billion annually, considering additional healthcare costs and productivity losses [4]. Globally, it is predicted that by 2050, AMR could cause annual economic losses of between USD 1 and 3.4 trillion due to increased healthcare costs and reduced productivity [4,5]. These data highlight the urgency of taking effective measures to combat AMR to protect public health while mitigating the associated economic consequences. Drugs fall into several categories: (i) Antibiotics, frequently detected because of their widespread use in human and veterinary medicine; examples include ciprofloxacin, sulfamethoxazole, and tetracycline. (ii) Analgesics and anti-inflammatories such as ibuprofen, diclofenac, and naproxen, which are commonly found because of their widespread use to relieve pain and inflammation. (iii) Antidepressants such as fluoxetine (Prozac) and sertraline (Zoloft), frequently detected in water bodies. (iv) Beta-blockers such as propranolol and metoprolol; drugs used to treat cardiovascular disease are also commonly found. (v) Synthetic hormones such as ethinylestradiol, used in contraceptives, are often detected, and can have significant ecological effects. (vi) Fever and pain relievers, which are among the most commonly prescribed drugs [6]. Many of these drugs are not effectively removed from sewage [7]. Naproxen, for example, is one of the most prescribed drugs worldwide. Several studies demonstrated the inability to effectively remove naproxen by conventional water treatment processes. Furthermore, its biodegradation in the environment is less efficient when compared with other drugs [6]. Conventional wastewater treatment plants (WWTPs) proved ineffective in removing most drugs, such as diclofenac, because of their physical–chemical properties [8,9]. Moreover, in light of these important steps towards more resource-conscious management, conventional WWTPs are limited in energy cost, which can be as low as 2.1 kWh per m³ of treated effluent [10]. The capacity to remove classical contaminants, such as Biochemical Oxygen Demand (BOD5), Chemical Oxygen Demand (COD), and Total Suspended Solids (TSS), remains acceptable at 93% BOD5, 92% COD, and TSS 94%, while for nutrients such as Total Nitrogen (TN) and Total Phosphorus (TP), the elimination rate is lower at 28% and 56% [11]. To address this issue, the NORMAN project was founded in 2005. This project by the European Commission collected data on emerging pollutants to facilitate data exchange on this matter. After 10 years of work, it was stated clearly that exposure to emerging chemical pollutants needs to be assessed comprehensively, considering their impact on human health [12]. The main concern is the worldwide increase in drug consumption, which could lead pharmaceutical residues in surface water to reach concentrations capable of producing adverse effects on humans and the environment [13]. Among the consequences of this phenomenon, the proliferation of antimicrobial resistance represents an especially critical issue, being increasingly recognized at the international level as a priority for global health policy [14]. Drugs and their metabolites enter the environment primarily through excretion and improper handling after their disposal [15]. Despite their origin, the highest concentrations of these compounds are typically found in WWTPs [16]. Due to their incomplete disposal, residues of potentially toxic organic compounds, including drug products, are often detected in surface waters. Municipal and hospital sewage are the primary sources of human drug contamination, supplemented by contributions from drug manufacturers, landfill leachates, and unused medications disposal. For veterinary drugs, the main environmental pathways include agricultural applications with subsequent runoff and direct use in aquaculture systems [17].

One of the Sustainable Development Goals of The UN Agenda 2030 is to improve wastewater treatment plants, but the current state does not guarantee the proper removal of these emerging contaminants. The EU Taxonomy includes activities that can contribute positively to protecting water resources and marine waters, such as reusing purified water. This represents a key tool for achieving the Sustainable Development Goals (SDGs) of the 2030 Agenda [18,19]. A further step toward progress in this field is the European Directive 2024/3019 on Urban Wastewater Treatment, which envisions the introduction of quaternary treatment specifically for micropollutants, including drugs, by 2045. In order to prevent and reduce their negative impact, the European Council, in a revised Directive, adopted a new provision related to additional “quaternary treatment” for micropollutants, which will be mandatory for WWTPs with 200,000 population equivalents and more by 2045 [20]. This is part of the European Zero Pollution Plan and aims to safeguard humans and the environment [21]. In this context, the use of algae-based systems would fulfill several points addressed by the Zero Pollution policy, particularly the recovery of nutrients lost to the environment, the clearance of emerging contaminants, and the reduction in the use of chemical agents for water purification.

This review provides a comprehensive and integrative analysis of microalgal systems and algal–bacterial consortia, with a distinctive focus on the comparative evaluation of the species involved, the underlying metabolic pathways, the broader implications for environmental sustainability, and the emerging bioeconomy. Emphasis is placed on microalgae systems, whose pollutant-removal capacities have been validated through a wide range of experimental and pilot studies [22,23]. The work begins with an assessment of the current performance and limitations of WWTPs, followed by an evaluation of cost-efficiency, performance, and alignment with long-term sustainability goals.

2. Research Strategies and Bibliographic Sources

This review focuses on the most recent research to (i) assess the current drugs environmental fate; (ii) provide useful information for future research.

For this review, we performed bibliographic research using some of the most influential scientific search engines—Google Scholar, ResearchGate, Scopus, PubMed, SpringerLink, Web of Science, and ScienceDirect—by entering several keywords, i.e., pharmaceuticals, wastewater, microalgae, WWTPs, consortia, biomass recovery, gene expression, and phytoremediation.

3. Quantitative Data on Drugs as Emerging Contaminants

As mentioned earlier, the use of drugs has increased exponentially in recent years for both human health and animal husbandry and agriculture, all of which have an impact on WWTPs [24]. As a result, researchers have focused their attention on the qualitative and quantitative evaluation of the drugs present and the effectiveness of current purification steps [25,26].

European pharmaceutical prescriptions varies significantly by region because of many interacting factors. Prescription patterns in Lombardy and Campania’s Local Health Units (LHUs) were analyzed in an Italian study for the EDU.RE.DRUG project [27]. The results indicated greater prescription prevalence in Campania versus Lombardy, particularly for antibiotics, proton pump inhibitors, and respiratory medications. Geographic location significantly predicted prescription rates in multivariate regression, independent of general practitioners, demographics, and patient age [27]. A Swedish study of almost nine hundred thousand people over ten years found that patient demand, not regional supply factors, largely explains variations in drug spending. The study estimates that individual health needs and behaviors, and not regional supply, are the primary drivers of drug spending variation (90–95%) [28].

Massano et al. (2023) compiled a list of the 105 drugs most found in Italian effluents to have a complete overview of WWTPs’ quality across the country [29]; they pointed out that even the detection systems for these ECs within our waters are still technologically backward. The presence of drugs in sewage is a truly diverse phenomenon that depends very much on their area of origin and the type of population [29]. For example, among the drug prescriptions, Non-Steroidal Anti-Inflammatory Drug (NSAIDs) and cardiovascular are mostly prescribed in the southern regions, e.g., Campania, while antidepressant and antipsychotic drugs are the most represented in the northern areas of the country. Rapp-Wright et al. (2023) monitored the state of WWTPs in the UK and Ireland [30]. Among the 140 substances listed in the European Water Framework Directive (EU-WFD) watchlist, antibiotics accounted for approximately 20% of the detected pharmaceuticals. Notably, sulfamethoxazole, sulphapyridine, trimethoprim, and ciprofloxacin were quantified at concentrations of 44 (±23), 81 (±67), 228 (±197), and 6 (±2) ng·L⁻¹, respectively, representing 6% of all compounds analyzed. In surface waters, by contrast, antibiotic levels were either negligible or below quantification limits, with ciprofloxacin being the only compound detected in urban areas, where it reached up to 5 (±26) ng·L⁻¹. Antihypertensive agents also exhibited low concentrations relative to wastewater levels. For instance, hydrochlorothiazide was found at a maximum of 18 (±25) ng·L⁻¹ in urban surface waters. Similarly, valsartan, one of the most commonly prescribed antihypertensives, was detected in sewage at mean concentrations of 2894 (±2283) ng·L⁻¹ in rural areas and 2423 (±821) ng·L⁻¹ in urban settings, but was absent in receiving waters, likely due to dilution and/or the high removal efficiency of wastewater treatment processes [30]. A study conducted by Khasawneh (2021) assessed the concentrations of drugs in the influents of the Asian region and discovered that acetaminophen and atenolol were the most present (respectively, 473 and 592 g·1000 in⁻¹·d⁻¹), while amoxicillin and sulfamethoxazole had the most daily emissions [31]. The presence of these compounds in water may pose a risk; for example, Giunchi et al. found a high risk with a predicted no-effect concentration (PNEC) for three antibiotics—which were ciprofloxacin: 73.33 average in three years, amoxicillin: 28.79 in three years, and azithromycin: 10.75—and one anti-inflammatory agent, diclofenac: 17.42. They also found a moderate risk for antibiotic clarithromycin: 3.47 (all the results are expressed as an average of the three years of observation from 2019 to 2021) [32]. Makowska et al. (2024) evaluated the fate of drugs added in therapeutic doses in discharged water. However, there were non-toxic effects present in the activated sludge, residual drugs, and their metabolites, and their entry into the environment could pose a risk [33]. These studies show that regional prescription differences are complex and influenced by patient traits and healthcare systems.

3.1. Wastewater Treatment Plant and Their Challenges

There are several biological systems, e.g., membrane bioreactors, activated sludge, biofilm reactors, and constructed wetlands [34,35]. With these technologies, we can produce better-depurated effluents. Drugs are usually removed via biodegradation and photodegradation [3]. Biodegradation can be achieved through different microorganisms; this is the reason they could be integrated into WWTP’s biological processes. Biodegradation is usually achieved anaerobically. Several chemical techniques exist, including anaerobic filters, film reactors, sludge reactors, sequential batch reactors, and membrane batch reactors, for that purpose. Moreover, systems involving consortia with bacteria lower the total cost even more with the production of an environmentally safer outcome [34,36,37,38,39]. A WWTP is a complex system designed to restore water that is safe for reuse to the environment. It consists of various processes designed to chemically, physically, and biologically reduce pollutant presence [40]. These technologies are wasteful in both energy and economic terms, hence the constant search for alternative and more effective methods. A very promising alternative that has been studied for years [41], compared to conventional technologies, is the integration of algae [42] and algal–bacterial consortia (ABC) [43]. In this review, three distinct species will be analyzed: two green algae, Chlorella spp. and Scenedesmus spp., for their known capabilities in pharmaceutical depletion; and the extremophile red alga Galdieria spp. as a promising candidate for its unique properties. These three were selected because they are among the most studied and are considered valuable alternatives in phytoremediation [44,45,46,47,48,49]. The studies presented below describe the uses of resulting biomass in different scenarios: specifically developed experimental media, small pilot plants, and WWTPs. Studies will be presented on single drugs or mixtures of different compounds to evaluate their removal rates by individual organisms and potentially toxic effects on the same.

3.2. Algal Species-Specific Drug Removal Performance

Several studies have reported species-specific efficiencies and mechanisms in the disposal of pharmaceuticals by microalgae as reported in

Table 1. Commonly found drugs’ elimination rate by algal system.

Drug	Class	Species/Genus	Mechanism	Removal Efficiency	Ref.
Sulfamethoxazole	Antibiotic	C. sorokiniana	Bioaccumulation + Biodegradation	99%	[53]
Ciprofloxacin	Antibiotic	C. sorokiniana	Bioaccumulation + Enzymatic degradation (CYP450)	100%	[53]
Diclofenac	NSAID	Chlorella spp., Scenedesmus spp.	Bioaccumulation, photodegradation, biodegradation	up to 99%	[54,55,56,57]
Ibuprofen	NSAID	C. vulgaris, Scenedesmus spp.	Bioaccumulation, biodegradation	up to 40%	[54,58]
Paracetamol (acetaminophen)	Analgesic	Chlorella spp.	Bioaccumulation, biodegradation	up to 90%	[54]
Metoprolol	Beta-blocker	Chlorella spp.	Bioaccumulation + Photodegradation	up to 60%	[54]
Estradiol (E2)	Steroid hormone	S. obliquus	Bioaccumulation + Biodegradation	99%	[59]
Estrone (E1)	Steroid hormone	S. obliquus	Bioaccumulation + Biodegradation	91%	[59]
Galaxolide	Synthetic fragrance	Scenedesmus spp., Chlorella spp.	Photodegradation	up to 99%	[54]
Tributyl phosphate	Plasticizer	Scenedesmus spp.	Volatilization	up to 99%	[54]
4-octylphenol	Surfactant/EDC	Scenedesmus spp.	Volatilization	up to 99%	[54]

. For instance, Scenedesmus obliquus has been shown to remove up to 99% of estradiol (E2) through intracellular enzymatic degradation, highlighting its potential for endocrine-disrupting compound (EDC) removal [50]. Similarly, Chlorella sorokiniana demonstrated complete elimination (100%) of ciprofloxacin, attributed to a combination of bioaccumulation and oxidative metabolism, likely involving cytochrome P450 enzymes [51]. In another case, Chlorella vulgaris cultivated in high-rate algal ponds (HRAPs) achieved up to 90% disposal of ibuprofen and paracetamol, driven by a mix of bioadsorption and photodegradation, particularly under extended hydraulic retention time and seasonal light conditions [52]. These examples underscore the importance of selecting specific strains according to the contaminant profile, in order to optimize the clearance efficiency of drugs and enable tailored strategies.

3.2.1. Scenedesmus spp. for Phytoremediation

Another promising candidate for such applications is the green microalgae Scenedesmus spp. [36,37,46,47] belonging to the class Chlorophyceae, renowned for its ecological adaptability and biotechnological potential. An important primary producer, it typically forms non-motile coenobia of four to eight cells and thrives in various aquatic environments [60]. It combines high biomass productivity with a composition rich in proteins, lipids, and carbohydrates. These characteristics make it a promising candidate for biofuel production, particularly biodiesel, as well as for food and food supplements. Among Scenedesmus spp., studies have shown that under nitrogen-deficient conditions, S. obliquus can accumulate lipids accounting for up to 60% of its dry weight, improving its suitability for biodiesel production [61]. Besides environmental applications, S. obliquus is used as a model organism in ecotoxicological studies. Its sensitivity to pollutants enables the assessment of water quality and environmental impact. For instance, it has been employed to evaluate the toxicological consequences of various contaminants, including heavy metals and organic compounds, shedding light on their ecological risks [60]. Scenedesmus spp. can remove nutrients and organic substrates and reduce CO₂ through photosynthesis; the latter is particularly convenient and commonly adopted in secondary and tertiary effluents [62,63]. Scenedesmus spp., particularly S. obliquus, exhibit mixotrophic growth capabilities by utilizing organic carbon sources to support their metabolism. Several studies have explored this cultivation strategy [64,65]. The resulting protein-rich biomass holds potential for application as a feed supplement in livestock and aquaculture sectors [66]. An alternative approach involves heterotrophic cultivation in closed, light-free systems, which has been shown to enhance cell density, alter biochemical composition, and improve biomass productivity compared to phototrophic conditions [67]. Under such conditions, nutrient removal efficiencies reached 81% for NH₄⁺, 100% for NO₃⁻, 94% for PO₄³⁻, and 71% for COD after 16 days. The harvested biomass contained 28.5% protein, 27.5% carbohydrates, and 26.5% lipids by dry weight [67].

Mixotrophic cultivation of Scenedesmus spp. in nutrient-rich environments has been shown to enhance biomass yield and modulate lipid and carbohydrate metabolic pathways, offering a sustainable approach to environmental remediation. However, the economic feasibility of large-scale biofuel production remains constrained by limited biomass productivity as well as elevated production and operational costs [68]. New methods of remediation using Scenedesmus have been developed in recent years. A recent study employed a membrane bioreactor system for the treatment of municipal effluents, aiming to decouple the solids’ retention time from the hydraulic retention time. This approach resulted in a 129.3% increase in the daily treated liquid volume and a 48.7% improvement in biomass productivity, reaching a final value of 22.2 ± 1.9 g·m⁻²·day⁻¹. Nutrient removal was strongly affected by the permeate flow rate, with phosphate removal reaching up to 0.65 mg·m⁻²·day⁻¹. The application of an ultrafiltration membrane enabled the removal of over 99% of ammonia, although this outcome was partly attributed to nitrate accumulation due to enhanced activity of nitrifying bacteria. Notably, higher permeation rates correlated with increased relative abundance of these bacteria. Based on these findings, a raceway pond system with a surface area of 1 hectare could potentially treat 2.58 million cubic meters of wastewater while generating 79.92 metric tons of biomass [69]. For chemical compounds, Scenedesmus spp. are well studied and known, with close to 100% of sequestration. The genus Scenedesmus has shown equally promising results. In consortia systems with Chlorella spp., it was able to remove a wide range of contaminants, including ibuprofen, which was removed by about 40% through biodegradation processes. Additionally, compounds such as 4-octylphenol, galaxolide, and tributyltin phosphate were removed with efficiencies close to 99%, primarily through volatilization processes [54]. Specific studies on S. obliquus reported 91% of estrone and 99% of estradiol elimination, both through intracellular biodegradation processes [55]. Scenedesmus quadricauda also proved to be highly efficient with estrogens, achieving up to 89% elimination through the combined action of photodegradation and released intracellular substances [70].

Other researchers uncovered that high removal rates for TN, TP (~90%), and COD (~70%) could be obtained if the system was provided with the best conditions [71]. The best strains for this purpose were S. obliquus and C. vulgaris, especially when removing diclofenac from culture media [72]. It also reported a 93% ciprofloxacin [56] and a 97% erythromycin rate of elimination with Scenedesmus spp. [57]. Among the strains studied, SD07 exhibited a good growth rate of 75% of municipal discharge as a growth medium and showed efficient COD, NH₄⁺, TN, and TP (88–96%) elimination. Harvested biomass had 35% protein, 20.4% carbohydrate, and 33% lipid content. These findings suggest that this Scenedesmus strain SD07 may be suitable for this purpose while producing valuable biomass [73]. The phytoremediation potential of the Scenedesmus genus has also been explored in S. subspicatus, which demonstrated the capacity to remove various pharmaceuticals including sulfamethoxazole from the culture medium. Among these, propranolol and sulfamethoxazole exhibited limited susceptibility to photolysis and hydrolysis, indicating that their removal was primarily attributable to the metabolic activity of S. subspicatus. In contrast, salicylic acid, albendazole, and atenolol were more readily biodegraded by the alga. Quinolone antibiotics such as ciprofloxacin, ofloxacin, and norfloxacin underwent partial degradation through a combination of phytoremediation and abiotic processes (i.e., photolysis and hydrolysis). The breakdown of these compounds was enhanced and accelerated under mixotrophic cultivation, particularly in the absence of HCO₃⁻ supplementation. However, a reduction in algal growth rate observed in the presence of the pharmaceutical mixture suggests a potential toxic effect associated with combined drug exposure [74].

3.2.2. Chlorella spp. for Phytoremediation

Chlorella is a single-cell green algae belonging to the Chlorophyta division and Trebouxiophyceae class, known for their high chlorophyll content, which makes them deep green. Chlorella spp. is often used as a dietary supplement for humans and livestock, as it is rich in protein, vitamins, minerals, and antioxidants. In addition, it is studied for its potential human health benefits, such as supporting the immune system and detoxifying the body [75]. C. vulgaris, known for its rapid growth rate and high photosynthetic efficiency, is viable for various biotechnological applications [76]. It has a high and rich biomass productivity, which is why it is being studied for applications such as the production of biofuels, especially biodiesel [77], because of their ability to accumulate lipids [78]. This alga can adapt to variable environmental conditions (fluctuations in pH, temperature, and light intensity), further increasing its suitability for large-scale cultivation. Advances in genetic engineering have also paved the way for optimizing its metabolic pathways to increase the yield of desired bio-products [79]. It is often studied because of its ability to sequester nutrients and pollutants from the environment [48,49,80]. Because of its ability to grow in various environments and its ability to degrade pollutants, Chlorella spp. is studied as an alternative to conventional processing; among its different species, C. vulgaris has been tested for the purification of effluents from anaerobic digestion, showing good ammonia and nitrogen elimination capacity as well as biomass production [49,81]. The growth of C. vulgaris was studied in winnowing sewage, showing that it can grow even in the presence of pollutants and microorganisms. These studies demonstrate the potential of Chlorella as a tool contributing to environmental sustainability [82]. The ability of Chlorella spp. to phytoremediate drug-contaminated aquatic environments has been evaluated by several studies on both freshwater and real sewage [83]. Similar to toxicity findings on Scenedesmus spp. [74], toxic effects were also observed for Chlorella spp. [84]. The study shows significant toxicity of the tested drugs ibuprofen and ciprofloxacin on C. vulgaris, reducing its growth with IC50s of 89.65 mg·L⁻¹ and 29.09 mg·L⁻¹, respectively. Mixtures of drugs generated greater toxic effects (IC50 of Ciprofloxacin + Ibuprofen 60.71 mg·L⁻¹) than individual compounds with synergistic effects, especially at low concentrations, implying that small doses of different substances may have a greater impact than expected, with dangerous consequences for the environment. Although the environmental concentrations of individual drugs may be low, their simultaneous presence may be significant. The authors emphasize the need to consider these combined effects in risk assessment [84]. Phytoremediation can be affected by various elements (strain adopted, contaminant characteristics, environmental conditions) [85]. Chlorella genus, for example, demonstrated extraordinary efficiency against antibiotics, achieving a 99.3% removal of sulfamethoxazole (SMX) and a complete removal (100%) of ciprofloxacin. These results were achieved through a synergistic combination of biodegradation and molecular transformation processes [53]. The same strain was also successfully employed in the degradation of other contaminants such as diclofenac, ibuprofen, paracetamol, and metoprolol, with efficiencies of between 60% and 100%, thanks to the interaction between photolysis and enzymatic biodegradation [86]. C. vulgaris was also effectively used in HRAP on a pilot scale, where it was able to remove up to 90% of caffeine, acetaminophen (paracetamol), and ibuprofen from municipal discharge. The study described by Reddy et al. (2021) shows that the performance was particularly high during winter periods, when longer hydraulic retention times favored assimilation and transformation processes [54].

Certain microalgal strains, particularly Chlorella vulgaris and Scenedesmus obliquus, have demonstrated performances comparable to conventional treatment methods in terms of pharmaceutical degradation and the associated reduction in environmental risks; however, understanding their metabolism remains a challenge [87]. Due to their strong adsorption capabilities, they can be employed as waste adsorbents for removing antibiotics from water [58]. Al-Mashhadani et al. demonstrated that the biosorption efficiency of ciprofloxacin is significantly influenced by contact time, pH, and the concentration of the adsorbent. Under optimal conditions, specifically using 2.75 g·L⁻¹ of Chlorella vulgaris biomass, a contact time of 120 min, and a neutral pH of 7, a removal efficiency of 89.9% was achieved. Concurrently, a reduction in carbon, nitrogen, and phosphorus concentrations in the wastewater was also observed [58].

Table 2. Optimal cultivation parameters for different species.

Algae	pH	Temp (°C)	Cultivation Mode	References
Scenedesmus spp.	7	20–30 °C	Mixotrophic, phototrophic, heterotrophic	[61,67,69,87]
Chlorella spp.	6.5–8	25–30 °C	Phototrophic, heterotrophic	[58,76,78,81,82]
Galdieria spp.	1.5–4	Up to 56 °C	Autotrophic, heterotrophic, mixotrophic	[59,88,89,90,91]
ABC	Depends on system	Ambient (variable)	Self-regulating in photobioreactors	[92,93,94,95,96]

summarizes the main biological and cultivation characteristics of the three algae considered in our study.

3.2.3. Galdieria spp. Potential in Phytoremediation

Galdieria spp. consists of species and strains belonging to different collections, some of which have been recently renamed (G. daedala strain ACUF 427, for example, was previously known as G. sulphuraria) [88]. These are a group of extremophile thermo-acidophilic species from the Cyanidiophyceae (phylum Rhodophyta) class, characterized by its high adaptability to extreme environmental conditions. It thrives under conditions of elevated temperature (up to 56 °C) and low acidity (pH 1.5), such as in sulfurous geothermal springs, and it can exploit different growth strategies: autotrophic, heterotrophic, and mixotrophic in both aerobic and anaerobic environments utilizing a wide variety of carbon sources. Galdieria spp. is recognized for producing bioactive compounds, such as phycobiliproteins (e.g., C-phycocyanin), and it is studied for its antioxidant, antibacterial, and anticancer properties. These compounds have significant implications for the pharmaceutical and nutraceutical industries. Furthermore, the capacity to accumulate glycogen up to 50% of its dry cell weight under mixotrophic conditions offers opportunities for use as an alternative to starch in various industrial applications [89,90].

Moreover, it has the capacity to extract rare earth elements from both mining and electronic waste [89,97]. Because of its proven ability to remove pollutants and pathogens from effluents, Galdieria spp. (G. sulphuraria, G. javensis) also appears to be promising for applications on ECs. There are several studies in the literature on this subject, and some pilot plants have also been conducted worldwide [44,45,98]. At present, the challenge is precisely to find the best integration system within existing plants. As mentioned earlier, Galdieria spp. (G. sulphuraria, G. javensis and G. daedala) can remove nutrients (phosphates, nitrogen, and carbons), pathogens, and heavy metals from various sources thanks to their ability to grow in different modes [89]. In addition, being an extremophile algae capable of adapting to very acidic pH conditions (1.5–4.0) and very high temperatures (up to 56 °C), a concomitant reduction in pathogens present in the water treated with the alga was observed, the conditions favoring even more the growth of G. sulphuraria at the expense of the bacteria present [91]. In summary, its high adaptability, as well as the extreme conditions in which the effluent can be maintained, make it a perfect candidate for applications in WWTPs. As stated earlier, the effectiveness of G. sulphuraria as a means of removing contaminants is extensively studied in the scientific community [59]. Pilot-scale plants are also applied in urban WWTPs, such as the POWER system established in Las Cruces, New Mexico. For 7 years, this system was evaluated and monitored to evaluate its efficiency, practicability, energy recovery, and overall performance. A significant reduction in pathogens and sequestration of nutrients could be observed, particularly for the bacterial load, especially coliform, and viral load [91]. In the study by Delanka-Pedige et al. (2020), the evolution of the viral community was evaluated [99], and a comparison was made between the POWER system and the conventional process: (i) POWER process could reduce the viral load in a single step without the traditional chlorination phase; (ii) much lower diversity into the viral community with this new method [99]. Regarding nutrient removal, the study reported that Chlorella vulgaris removed 4.8 mg·L⁻¹·day⁻¹ of ammonium and 1.21 mg·L⁻¹·day⁻¹ of phosphate from sewage. The biomass yield in the primary effluent, calculated based on nitrogen uptake, was 27.4 g of biomass per gram of nitrogen removed, exceeding the theoretical yield by over 70% and surpassing the average values reported in the literature for other microalgal species by nearly 10% [98]. Comparing growth performance in closed photobioreactors (PBRs) such as the POWER system against open pond systems, final cell densities in the former were 3 to 5 times higher than those achieved in an open pond system [98], underlining the effectiveness of this type of approach for biomass harvesting, with lower energy costs in the drying stage [98]. This significant result indicated feasibility of the cultivation of microalgae in discharged waste, a process that offers the benefit of reduced energy expenditure. The adaptability of Galdieria spp. in removing drugs in these contexts remains to be demonstrated. However, studies point to Galdieria spp. as being capable of removing antibiotics from the environment; evidence suggests that this system is more effective than conventional treatment methods in reducing concentrations of erythromycin- and sulfamethoxazole-resistant bacteria. Moreover, a declining trend was observed in both total bacterial abundance and the prevalence of antibiotic resistance genes [100]. Other studies, which arose in the aftermath of the COVID-19 pandemic, showed how G. sulphuraria could lower the viral load of urban sewage [97,101,102]. Due to its extremophilic properties, G. sulphuraria is regarded as a potentially effective pathogen remover. As demonstrated by Ambrosino et al. (2023), significant antiviral properties were identified, particularly against members of the Herpesviridae and Coronaviridae families [97]. Furthermore, the findings indicate that the combination could prevent the infection of enveloped viruses by inflicting substantial damage to the viral envelope. In addition, it plays a pivotal role in environmental remediation from various sources. Recent findings indicate that immobilized microalgae systems hold considerable promise for the remediation of toxic contaminants. Due to their compact design, these systems generate reduced sludge volumes and offer easier maintenance compared to larger fluidized bed configurations [103,104]. Although Galdieria spp. have not yet been directly studied for pharmaceutical elimination, their physiological and metabolic characteristics suggest potential applicability. Members of the genus Galdieria exhibit extraordinary tolerance to extreme pH and temperatures, and they have been successfully employed in the reduction in heavy metals and pathogens, including viruses. Based on these attributes, the use of Galdieria spp. against drugs remains a theoretical proposition that warrants further experimental validation. This section thus aims to present Galdieria spp. as a compelling candidate for future investigation in the emerging field of pharmaceutical bioremediation.

3.2.4. Other Notably Algae Species Used in Phytoremediation

Besides the well-known genera Chlorella and Scenedesmus, which have been extensively studied for their capabilities versus antibiotics from UW, recent studies also highlight the use of other species with interesting potential in this area. For example, Coelastrella spp. has been cited for its rapid growth and adaptability to different environmental conditions. It has demonstrated notable capabilities in accumulating and transforming antibiotic compounds, though it remains less extensively studied than more well-established organisms [36]. Desmodesmus spp. has been the focus of recent research because of its notable associations with Scenedesmus spp. and its capacity for elevated contaminant tolerance in specific environments. This species exhibits a high-efficiency level in removing tetracyclines and sulfonamides, a property observed in both batch and semicontinuous systems [39]. Similarly, Ankistrodesmus spp. has demonstrated significant efficacy in the initial stage of antibiotic adsorption. Although species belonging to Monoraphidium spp. and Dictyosphaerium spp. have been investigated for their efficacy within consortia systems where interactions with bacteria contribute to enhancing process stability and broadening the range of activated elimination mechanisms, their potential in such integrated approaches remains underexplored compared to other genera. Furthermore, Leng et al. (2020) also mention the experimental use of strains belonging to Spirulina (Arthrospira spp.), which, although primarily known for nutraceutical applications, have shown some ability to sequester antibiotics through biosorption mechanisms [37].

In conclusion, Botryococcus spp. have been evaluated for their robustness and high lipid content, which could allow efficient biomass recovery downstream of the process. While these species have yet to assume a dominant role in large-scale application, they constitute a captivating reservoir of functional biodiversity. The exploration of this reservoir could unravel substantial improvements in the efficiency and versatility of phytoremediation systems.

3.3. Mechanisms and Applications of Algal–Bacterial Consortia

Algal–bacterial consortia (ABC) offer a compelling and efficient solution for addressing wastewater-related challenges [105,106,107]. These systems capitalize on the synergistic interactions between algae and bacteria, which collaborate metabolically to eliminate a variety of contaminants. For instance, Gong et al. illustrated how the mutual exchange of nutrient substrates between these microorganisms optimizes their growth within such integrated systems [108]. This symbiosis not only promotes cooperative pollutant mitigation [37,109] but also contributes to the reduction in greenhouse gas emissions, thereby improving the environmental performance of WWTPs [109,110,111]. In some configurations, these organisms form biofilms that demonstrate heightened resilience to toxic compounds and further enhance efficiency [37,109]. A notable benefit of this partnership is the algae’s consistent nutrient uptake, even in the presence of pharmaceutical pollutants. As shown by Zaytsev et al., this stability is due to bacterial communities breaking down organic materials, making nutrients more accessible [92,112]. Because of this synergy, such processes have shown exceptional promise in WWTPs for the management of organic pollutants, excess nutrients (e.g., nitrogen and phosphorus), and trace metals. While bacteria play a pivotal role in degrading complex organics, algae contribute by assimilating or transforming contaminants, including pharmaceutical residues. Notably, the growth and nutrient-processing capabilities of Chlorella vulgaris are significantly enhanced in photobioreactors co-inhabited by bacteria and fungi. Chai et al. demonstrated that such tripartite systems achieved impressive removal rates: 93.71% for total nitrogen (TN), 93.56% for total phosphorus (TP), and up to 99.46% for antibiotics like oxytetracycline, along with high effectiveness for ciprofloxacin and sulfadiazine [92]. The coordinated microbial activity supports the breakdown of organic substances, leading to substantial reductions in chemical (COD) and biochemical oxygen demand (BOD). Studies consistently showed that consortia involving C. vulgaris and nitrifying bacteria can achieve nutrient reduction efficiencies surpassing 90% [93,94,104,111]. Further investigations, such as those by Kiki et al., revealed that the microbial community within activated sludge is reshaped by algal presence, which in turn facilitates the degradation of pharmaceutical agents and additionally can attenuate the prevalence of antibiotic resistance genes within these communities [113]. High-rate algae–bacteria ponds have proven effective for managing micropollutants commonly missed by conventional processing [114]. A seasonal analysis of 81 drug-related compounds treated by a Chlorella–Scenedesmus consortium highlighted consistent effectiveness against NSAIDs such as ibuprofen, with variable efficacy for others like salicylic acid depending on seasonal conditions. Beta-blockers like atenolol and diltiazem were efficiently processed (80% and ~75%, respectively), while fluoroquinolones such as ciprofloxacin reached near-complete disposal in the latter part of the year. Azithromycin and erythromycin were also efficiently cleared (~80%) [95]. Xiong et al. (2021) emphasized the superior performance of these hybrid systems in addressing antibiotics like sulfamethoxazole, tetracycline, and ciprofloxacin [39]. Their enhanced diversity in metabolic pathways expands the range of degradable substances, and the use of closed photobioreactors further optimizes operational control and enables biomass recovery for biotechnological purposes. These systems are particularly adept at targeting persistent compounds, including pharmaceuticals, hormones, and personal care products that are often resistant to traditional methods [96]. Nonetheless, challenges to widespread application persist. These include sensitivity to environmental fluctuations and the need for further research to standardize commercial implementation. Currently, applications within WWTPs focus on photobioreactors (PBRs) equipped with controlled lighting and CO₂ supplementation, which support optimal growth [43,115]. PBRs offer contamination-free environments and precise regulation of growth conditions (light, CO₂, temperature, pH), enabling energy-efficient pollutant reduction via assimilation, biosorption, and photosynthesis [39,85,116,117,118,119,120,121]. However, artificial lighting and gas supply in low-light scenarios can increase operational costs. While monocultures yield purer biomass, they are more vulnerable to contamination and require stricter management [39,116,117,118,119,120,121]. The implementation of ABC in semi-closed or open systems yields multiple advantages. Through photosynthesis, oxygen is generated and sustains bacterial metabolism, while bacteria mineralize organic waste and generate nutrients like CO₂. This collaboration significantly improves the outcome [108]. In these systems, diverse bacterial taxa including Flavobacterium, Acinetobacter, Bacillus, and Pseudomonas contribute to enhanced nutrient cycling and pharmaceutical degradation [53]. Individual strains have also demonstrated notable efficacy. For instance, Bacillus thuringiensis degrades ibuprofen via monooxygenase pathways; Pseudomonas putida breaks down paracetamol and salicylic acid oxidatively; Rhodococcus ruber targets diclofenac through dehydrogenase activity. Fluoroquinolone antibiotics like ciprofloxacin and norfloxacin are metabolized by Labrys portucalensis and Microbacterium spp., respectively, via mechanisms such as ring defluorination and hydroxylation [98]. Mixed consortia involving Enterobacter hormaechei, Citrobacter youngae, Achromobacter spp., and Pseudomonas spp. can disrupt various antibiotic and anti-inflammatory drugs. Beyond detoxification, ABC also enhances nutrient management through integrated algal assimilation and bacterial nitrification/denitrification. This interaction supports pollutant breakdown while minimizing the need for mechanical aeration due to photosynthetically derived oxygen, increasing energy efficiency. Their tolerance to variable light conditions boosts system robustness. Although the biomass produced in these consortia is less refined, it is suitable for downstream uses such as biogas production, composting, and soil enrichment. Importantly, studies suggest these systems can yield high-quality biodiesel, underscoring their economic and environmental value [43,94,122,123,124,125,126].

Table 3. Monoculture alga PBR vs. algal–bacterial consortia. Data adapted from [43,94,122,123,124,125,126].

Feature	PBR Alga	PBR Consortia
Control Requirements	Precise control of light, temperature, CO2, and hydraulic retention time	More robust and adaptable to variable environmental conditions
Maintenance	High maintenance costs; risk of contamination without bacteria	Simpler maintenance compared to monoculture systems
Scalability	Limited scalability because of high construction and operational costs	Scalable and cost-effective for large-scale applications
Best-Use Case	Small-scale applications or high-value biomass production	Large-scale
Sustainability	Highly sustainable with renewable energy	Lower environmental footprint overall

summarizes the main characteristics of classic and consortia PBRs.

3.4. Antibiotic Disruption Mechanism by Algae

Microalgae represent a strategic biotechnological resource in addressing emerging contaminants through a coordinated set of biochemical and physiological mechanisms that include bioadsorption, bioaccumulation, extracellular degradation, and photodegradation [127]. The efficacy of these processes may vary depending on the species, the chemical structure of the target drug, and environmental conditions.

3.4.1. Superficial Adsorption and Intracellular Bioaccumulation

One of the main mechanisms adopted is the adsorption on the cell surface, often followed by intracellular bioaccumulation.

Bioadsorption is an initial extracellular process by which contaminant molecules are adsorbed onto the surface of the cell wall. This consists of polymers such as cellulose, glycans, and chitin, enriched with negatively charged functional groups (carboxyl, phosphoryl, and amine), which attract cationic contaminants. This mechanism has been observed, for example, in Chlorella spp. and Scenedesmus spp., which are particularly effective against amphoteric or basic drugs, such as ciprofloxacin and some NSAIDs [54,86].

In the case of Chlorella vulgaris, which was used in pilot-scale HRAPs, bioadsorption contributed significantly to the reduction in ibuprofen and paracetamol, especially under low temperature conditions and prolonged hydraulic retention times [53].

The adsorption process is mainly influenced by the cell wall’s surface charge, the medium’s pH, and the antibiotic’s chemical nature. The role of adsorption as a key mechanism in removing ciprofloxacin and sulfadiazine was investigated, and the efficiency varies depending on the species and the chemical structure of the contaminant. In particular, the study showed that adsorption was the dominant mechanism for ciprofloxacin under many of the experimental conditions analyzed [38]. Furthermore, the importance of adsorption as a first crucial step has been confirmed, indicating that this process can account for 60% of total reduction for some compounds [36].

Bioaccumulation is the process by which adsorbed molecules cross the cell membrane and are sequestered within the cell. As hypothesized, bioaccumulation can occur via passive or active transport, with the possibility of subsequent metabolic processes. In the presence of specific strains with a high affinity for antibiotics, this mechanism contributes significantly to overall performance, especially for persistent compounds [39]. Lipophilic drugs with a high partition coefficient (logKow) can passively diffuse through cell membranes and accumulate in the cytoplasm. This process is crucial for molecules such as diclofenac, which was removed from C. sorokiniana in photobiological reactors by up to 100%, thanks to combined mechanisms of absorption and intracellular transformation [53]. SMX suffered a similar fate, with 99.3% elimination via bioaccumulation and subsequent biotransformation in the same species. S. obliquus showed a remarkable capacity for the accumulation and subsequent intracellular degradation of hormonal compounds such as estrone and estradiol, with reductions of 91% and 99%, respectively, suggesting a synergistic combination of bioaccumulation and active metabolism [53,55].

3.4.2. Biodegradation and Photodegradation

Biodegradation represents a critical step in the detoxification process of antibiotics. A considerable number of species possess the capacity to synthesize intracellular enzymes able to metabolize xenobiotic compounds. This process reduces the toxicity of byproducts, permitting them to be more easily assimilated or less harmful [37]. Moreover, it is also important to emphasize that the degradation capacity exhibits significant variation depending on the strain, and the type of antibiotic, with environmental factors such as light intensity and nutrient availability capable of modulating the process’s effectiveness [39].

C. sorokiniana has been shown to possess enzymatic activity associated with cytochromes P450 (phase I), which facilitate oxidations, hydroxylations, and demethylation of compounds such as ciprofloxacin and diclofenac [86]. Subsequently, phase II enzymes such as glutathione-S-transferase conjugate the oxidized metabolites with water-soluble molecules, enabling excretion. In consortia environments, Chlorella spp. and Scenedesmus spp. showed a synergistic reduction in ibuprofen and paracetamol, due to the combination of primary metabolism and contaminant-induced co-metabolism activity [86].

Photodegradation is an additional mechanism that occurs through the presence of light (natural or artificial), stimulating photochemical reactions that lead to the breakdown of antibiotic molecules. The intensity of light can exert a substantial influence on the efficiency with which certain classes of antibiotics are removed, particularly fluoroquinolones. In the presence of photosynthetic pigments, microalgae can also act as catalysts for photo-oxidative reactions, thereby enhancing the efficiency of the degradation of recalcitrant compounds [36]. Photodegradation acts as a complementary process, enhanced by exposure to sunlight or artificial light, especially in open systems. The capability to produce photosensitive metabolites or catalyze the production of reactive oxygen species (ROS), which interact with contaminants. S. quadricauda, in particular, showed a high efficiency (up to 89%) in removing estrogens through a combination of photodegradation and release of reactive intracellular compounds [70]. Chlorella spp. also contributed to the photodegradation of persistent molecules such as metoprolol and galaxolide in semi-contained reactors, acting in combination with volatilization processes [54].

3.4.3. Molecular and Genetic Responses to Pharmaceutical Contaminants: Detoxification Pathways and Adaptive Mechanisms

Exposure of microalgae to emerging contaminants, such as antibiotics and NSAIDs, involves a complex response at the molecular level, with profound changes in gene expression and epigenetic regulation. Such responses are crucial in enabling cells to adapt to hostile environmental conditions, often characterized by the presence of xenobiotic compounds, and to activate metabolic pathways aimed at detoxification, chemical transformation of contaminants and, in some cases, their utilization as an alternative carbon source.

Few studies have thoroughly investigated the changes in gene expression and metabolism of algae that determine their ability not only to adapt to unfavorable environments but also to allow the deletion of contaminants from the environment.

The study presented by Rempel et al. (2021) showed that, in response to drug exposure, increases in the expression of specific enzymes belonging to the phase I family, including cytochrome P450 could be observed. This enzyme complex promotes oxidation, hydroxylation, and molecular bond-breaking reactions, transforming hydrophobic compounds into metabolites that are more polar and thus more easily eliminated or further processed by the cell [86]. In a later phase, phase II enzymes such as glutathione-S-transferase come into play, which conjugate the reactive metabolites with glutathione or other endogenous substrates. This phase has a dual function: on the one hand, it neutralizes the oxidative potential of the reactive metabolites and, on the other hand, facilitates their excretion outside the cell [86].

In parallel with the activation of detoxification systems, algae respond to intracellular drug accumulation with a marked activation of the antioxidative response. The induction of oxidative stress, generated by the formation of ROS, involves the expression of genes encoding for superoxide dismutase (SOD) and catalase (CAT). These enzymes are essential for neutralizing ROS, thus protecting the cell from potentially irreversible damage to DNA, membrane lipids, and cytoplasmic proteins [53,86].

Finally, under conditions of prolonged environmental stress, epigenetic modifications are also observed to potentially have lasting effects on gene expression. In particular, Reddy et al. (2021) described the mobilization of transposable elements (TEs), i.e., mobile genetic sequences capable of inserting themselves into new genomic sites [54]. These events can induce mutations, alterations in gene expression patterns and phenotypic changes that result in increased resistance and their adaptability to chemical stresses. The ability to activate such mechanisms suggests adaptive evolution that allows some strains to survive and even thrive in drug-contaminated environments, taking an active role in their deletion.

With Chlorella spp., it was shown how the genes coding for N-acetyl-gamma-glutamyl-phosphate reductase, glycine hydroxymethyl transferase, and aldose 1-epimerase (arg56, glyA, and galM, respectively) are upregulated and how this may be a mechanism of adaptation to the environment, which is then necessary for adequate growth [128]. N-acetyl-gamma-glutamyl-phosphate reductase, glycine hydroxymethyl transferase, and aldose 1-epimerase (arg56, glyA, and galM, respectively) are upregulated. They are key metabolic enzymes with potential roles in the transformation of pollutants. Gene arg56 encodes N-acetyl-γ-glutamyl-phosphate reductase, an oxidoreductase involved in arginine biosynthesis that catalyzes reactions using NAD⁺ or NADP⁺ as electron acceptors. Although not directly involved in drug degradation, its increased activity may reflect a general regulation of redox metabolism, which supports oxidative degradation pathways. Gene glyA encodes glycine hydroxymethyltransferase, which catalyzes the conversion of glycine and 5,10-methylenetetrahydrofolate to serine. Serine can be oxidized to provide energy (2.53 kcal·g), supporting metabolically demanding processes. In particular, due to structural similarities between 5,10-methylenetetrahydrofolate and certain nitrogen-containing heterocycles present in drugs such as sulfamethoxazole or other sulphonamides, glyA may participate indirectly in their transformation. This enzyme has previously been associated with the biodegradation of roxarsone, suggesting a broader role in xenobiotic metabolism. Gene galM, which encodes aldose 1-epimerase (mutarotase), facilitates carbohydrate metabolism by catalyzing the interconversion between hexose sugars anomers; its upregulation may reflect increased central carbon metabolism, which may provide precursors and reducing the power required for co-metabolic transformation of organic contaminants [128].

Furthermore, Chlorella spp. can withstand nitrite-rich environments by modifying Citrate Synthase (CS) and Phosphofructokinase (PFK) enzymes involved in carbon metabolism [129]. C. vulgaris can increase glutathione reductase activity in response to the presence of antibiotics [130]. These evidence reinforce their biotechnological value as bioremediation agents, not only for their efficiency, but also for their molecular and genetic plasticity in response to the contaminated environment.

Exposure to pharmaceutical pollutants induces significant transcriptional responses, involving genes related to detoxification, oxidative stress, and energy metabolism. For example, Chlorella and Scenedesmus spp. have shown upregulation of phase I enzymes such as cytochrome P450 and phase II enzymes like glutathione-S-transferase, both crucial for xenobiotic metabolism. Additionally, antioxidant defense genes such as SOD and CAT are activated in response to reactive oxygen species generated during drug exposure. Transcriptomic analyses have further identified metabolic genes including arg56 (arginine metabolism), glyA (glycine cleavage), galM (galactose mutarotase), phosphofructokinase (PFK), and citrate synthase (CS), which may play roles in compensatory energy pathways or stress adaptation. These findings suggest a complex regulatory network underpinning these organisms’ resilience and pollutant transformation capacity.

3.5. Microalgae for the Green Transition

With the growing need for sustainable economic models, these organisms are emerging as versatile players in ecological transition, offering practical solutions to environmental problems and the challenges of the circular bioeconomy. Their ability to grow in marginal environments makes them ideal for the low-impact production of high-value biomass. Recent data have shown that the biomass grown in sewage reduces water footprints and carbon emissions, and can also be processed into renewable energy products such as bioethanol, biogas, and bioplastics, fostering a circular economy that values waste as a resource [131]. The importance of algae in sustainable effluent management and energy conversion is further explored. Kandasamy, S. et al. (2023) has provided an integrated view of the role of these microorganisms in nutrient sequestration, pollution mitigation, and energy production from biological sources. The authors indicate that these new technologies are developing rapidly and could be implemented on a large scale, especially in areas where there is high pressure on water resources [132]. In parallel, other researchers discussed said applications, highlighting how these solutions represent a strategic nexus to promote more sustainable industrial practices [133]. These organisms not only purify water but also accumulate bioactive compounds that are useful in the cosmetic, pharmaceutical, and nutraceutical sectors, thus reinforcing the concept of integrated bio-refinery [133]. At present, there are significant barriers to the direct use of such biomass grown in polluted environment for food, cosmetic, pharmaceutical, or nutraceutical purposes. These include potential contamination by pharmaceutical residues, heavy metals, and pathogens, as well as strict regulatory constraints imposed by agencies: Food and Drug Administration (FDA) and European Food Safety Authority (EFSA). Such biomass can be used in products intended for human or animal consumption requiring rigorous purification and safety validation, which often entails high processing costs and technical complexity. However, there are already examples of indirect or non-edible applications of this type of biomass. For instance, companies like All-Gas project (Spain) or Algae Systems, LLC (USA) that have commercialized such biomass to produce bioenergy from WW. These technologies represent a promising tool for the green transition, fostering synergies between environmental remediation, renewable energy generation, and sustainable circular economy development. Nevertheless, widespread deployment of these approaches will require continued investment in targeted research, improved technology transfer processes, and the development of robust regulatory and public engagement frameworks to ensure safety, acceptance, and scalability.

4. Future Directions

Although the technologies discussed certainly represent an environmentally friendly approach, there are still some crucial points to be resolved. First, one must consider the heterogeneity of municipal sewage in terms of their composition in nutrients and contaminants. One must also assess the interactions between the various drugs and other emerging contaminants, such as microplastics. Byproducts and degraded products after the process could also be toxic to aquatic fauna, as already investigated by some studies [134,135]. Another aspect is the variability in elements such as weather, light exposure, and control organisms’ populations that can significantly influence drug removal.

Although all the research works assessed for this review clearly demonstrated the viability of phytoremediation, some criticality remains to be addressed: in scenarios when the single species did not completely or partially remove some compounds, the use of consortia, since the elimination of the drugs is also compound/species-dependent, could be a solid alternative, although it still needs perfecting some key parameters as environmental conditions.

PBR are ideal for small-scale, high-purity applications, especially where high-value biomass products are the goal. However, they require precise control and may not be cost-effective. On the other hand, ABC are more suitable for large-scale applications because of their adaptability, scalability, and superior remediation capabilities. They are greener and more sustainable than conventional methods. There is no doubt that the methodologies examined in this review have numerous advantages, especially in removing emerging contaminants such as drugs and antibiotics while potentially producing clean energy simultaneously. However, wastewater is a heterogeneous mixture of different drugs and contaminants of distinct types that are susceptible to rapid changes because of light, temperature, and residence time in the system. The study of all these variables needs further investigation, especially from the point of view of the interactions between the various compartments and the optimal balance between algae and bacteria for maximum yield. Furthermore, as noted by Peng et al., the ecotoxicological risk from the degradation of certain drugs, such as tetracycline, oxytetracycline, and cephalosporin, which had more adverse effects than their parent compound, must also be considered [36].

Preliminary techno-economic assessments (TEA) suggest that systems like ABC and HRAPs can be cost-competitive with conventional methods under specific operational conditions [19,126].

Delanka-Pedige et al. (2021) examined the feasibility of systems for municipal effluent in the context of the SDG, highlighting their cost-competitiveness in nutrient and contaminant remediation [19]. Similarly, Vassalle et al. (2023) and Arashiro et al. (2022) indicated that HRAPs offer a cost-effective alternative for tertiary treatment under specific climate conditions [136,137].

However, challenges and limitations to overcome remain: (i) Maintaining operational stability with a balanced algae–bacteria ratio is critical for consistent performance, as environmental factors like light intensity, temperature, and pH can disrupt the system; (ii) while effective at the laboratory scale, scaling up these systems for large WWTPs requires significant infrastructure investment; (iii) efficient methods for harvesting biomass from treated water remain a technological bottleneck, which could be, however, overcome by using immobilized algae systems [104,138,139].

5. Conclusions

With this review, we demonstrated the feasibility of algae-based systems as a sustainable and energy-efficient approach to pollution management. These systems not only facilitate the effective elimination of several pollutants, nutrients, and emerging contaminants such as antibiotics and organic micropollutants but also offer synergistic benefits when integrated into existing infrastructures. While PBR are currently ideal for small-scale or low-polluted water applications, demonstrating particular efficacy in scenarios where precision control over environmental parameters is essential, consortia are more adaptable and cost-effective for large-scale plants. Their cooperative metabolic interactions enhance resilience, nutrient recovery, and system stability, making them particularly attractive for circular economy frameworks. Key advantages include superior remediation, reduced greenhouse gas emissions, and potential for biomass valorization. These additional valorization pathways offer promising avenues to improve the overall economic sustainability of the process. However, challenges remain, such as optimizing environmental conditions, scaling up systems, and improving biomass harvesting techniques. Despite the demonstrated efficacy, the fate of residual biomass remains a critical challenge. If not managed sustainably, this biomass can pose environmental risks by reintroducing pollutants. However, numerous studies have proposed its valorization into biofuels, fertilizers, or bioplastics, aligning with circular economy goals [19,77]. Addressing biomass disposal or reuse is essential for the holistic sustainability of these systems. Among the most critical are the optimization of operational parameters (e.g., light intensity, hydraulic retention time, pH, and CO₂ supplementation), the development of scalable and cost-effective harvesting technologies (such as low-energy flocculation or membrane separation systems), and the need for robust strategies to ensure year-round system performance under variable climatic conditions. Furthermore, regulatory frameworks and public acceptance of products derived from wastewater-grown biomass represent non-negligible hurdles that need to be systematically evaluated.

In conclusion, while these technologies are not yet universally applicable in all contexts, their integration into hybrid systems or tertiary steps appears promising. Continued research into system design, process integration, and TEA will be pivotal to bridge the gap between laboratory-scale success and full-scale implementation, perhaps even implementing the idea and concept of an ad hoc-designed closed PBR.