Search Results (331)

Background: Actinium-225 (²²⁵Ac) is receiving major attention as the radionuclide of choice for targeted alpha therapy (TAT) due to its outstanding physical properties such as a long physical half-life of 9.9 days and a short range of alpha (α)-particles which are responsible for the destruction of malignant tumors, whilst sparing normal surrounding tissues. Although the physical properties of ²²⁵Ac make it a desirable radionuclide for TAT, its application is challenging due to the lack of chelators available to stabilize its daughter radionuclides, resulting in the recoil effect. This occurs when there is a breakdown between the radionuclide and the chelator, therefore minimizing the therapeutic effects of the radiopharmaceutical. Nanodrug delivery systems (NDDSs) may minimize the challenge of ²²⁵Ac’s recoiling daughters and increase tumor penetration. Aim: This study aimed at using poly(lactic-co-glycolic)acid (PLGA) and chitosan (CS) nanoparticles as a delivery vehicle for targeted alpha therapy of prostate cancer in order to increase the therapeutic effect of ²²⁵Ac PSMA617-TFA. Methods and Results: PLGA nanoparticles were prepared using a nanoprecipitation method, after which they were functionalized with chitosan and folic acid. Following synthesis of ²²⁵Ac PSMA617-TFA, the radiopharmaceutical was loaded onto the nanoparticles. SEM analysis and FTIR were performed for characterization of the nanoparticles, and in-vitro drug release of ²²⁵Ac PSMA617-TFA at pH = 6.5 and pH = 7.4, respectively, was measured. The nanoparticles prepared had an average size of 200 nm and had a positive charge. This was further confirmed using a zetasizer and with scanning electron microscope (SEM) analysis. The PLGA-CS nanoparticles indicated a high encapsulation efficiency after 24 h. The results also showed a controlled release of ²²⁵Ac PSMA617-TFA over 72 h. The results of this study indicate that PLGA-CS nanoparticles are suitable for retaining ²²⁵Ac and its recoiling daughters (²²¹Fr and ²¹³Bi) at the tumor site, potentially providing a platform for future therapeutic evaluation. Conclusions: The results of this study indicate that PLGA-CS nanoparticles demonstrate feasibility as a drug delivery vehicle for ²²⁵Ac PSMA617-TFA, with effective retention of ²²⁵Ac and its decay daughters. However, biological validation through in vitro cellular studies and in vivo preclinical models is required before therapeutic effectiveness can be established. Full article

Background and Objectives: Neurological complications of SARS-CoV-2 infection frequently impair patients’ long-term quality of life. This study aimed to identify clinical and laboratory risk factors—including inflammatory markers and micronutrients—for the occurrence or worsening of neurocognitive disorders in long COVID patients. Materials and Methods: In this prospective observational study, patients presenting with long COVID neurological manifestations were stratified by baseline MoCA score into two groups (≥23 and <23). Clinical, laboratory (inflammatory markers, 25-hydroxy vitamin D, vitamin B12, folic acid), and neuroimaging assessments (global cortical atrophy scale, Fazekas score) were performed over 24 months. Propensity score matching (PSM) for age, gender, and neurological comorbidities yielded 54 patients per group. Results: In the MoCA ≥ 23 group, significant predictors of cognitive decline included severe COVID-19 (OR = 2.211, 95% CI = 1.819–5.973, p = 0.012), autoimmune comorbidities (OR = 1.676, 95% CI = 1.191–2.390, p = 0.043), and elevated neutrophil-to-lymphocyte ratio (NLR; OR = 1.586, 95% CI = 1.431–2.122, p = 0.011). In the MoCA < 23 group, independent predictors were diabetes mellitus (OR = 3.021, 95% CI = 2.65–14.004, p = 0.016), autoimmune comorbidities (OR = 4.987, 95% CI = 1.412–6.033, p = 0.021), and NLR (OR = 5.944, 95% CI = 2.353–19.321, p = 0.015). Serum vitamin D levels were significantly associated with MoCA scores in both groups. Conclusions: COVID-19 severity, autoimmune comorbidities, NLR, and serum vitamin D represent key risk factors for neurocognitive decline in long COVID, highlighting potential targets for early intervention. Full article

Folate is a central nutrient in one-carbon metabolism, contributing to nucleotide biosynthesis, methionine cycling, methyl-donor supply, and epigenetic regulation. In animals, the intestine is both a principal site of folate absorption and a key target organ for folate action. This narrative review focuses primarily on livestock, poultry, aquaculture species, ruminants, and animal-source food enrichment, while also using rodent, human, and in vitro studies as mechanistic or translational evidence. We synthesize evidence on folate absorption, transport, and metabolism and evaluate the mechanisms through which folate influences intestinal health. Available evidence suggests that adequate folate supply may support epithelial renewal, tight-junction integrity, mucosal immune balance, antioxidant capacity, gut microbiota stability, short-chain fatty acid production, and epigenetic regulation of intestinal development. These effects have been reported in poultry, pigs, fish, ruminants, rodents, and maternal–offspring models. However, the evidence is uneven across species, and dose–response relationships, folate forms, bioavailability, and species-specific requirements remain major limitations for translating current knowledge into animal production. Future studies should compare folic acid, 5-methyltetrahydrofolate, natural reduced folates, microbiota-derived folate, and folate-producing probiotics; quantify the contribution of microbiota-derived folate to host methyl-donor pools; and develop precision strategies that integrate folate with other one-carbon nutrients, probiotics, and product-enrichment technologies. Full article

Background: Glioblastoma (GBM) remains a lethal malignancy due to temozolomide (TMZ) resistance and limited drug penetration across the blood–brain barrier, largely driven by hyperactive DNA damage repair mechanisms such as poly (ADP-ribose) polymerase (PARP). To address these challenges, we developed folic acid-targeted PLGA–zein hybrid core–shell nanoparticles for the codelivery of the alkylating agent TMZ and the natural PARP inhibitor Ellagic acid (FA-TMZ/EA-PZ-CS NPs), thereby enabling simultaneous enhancement of drug delivery and suppression of chemoresistance pathways. Methods and Results: The dual-drug nanoplatform was fabricated using a double-emulsion solvent evaporation method and functionalized via EDC/NHS-mediated folic acid conjugation to promote receptor-mediated uptake. Physicochemical characterisation confirmed uniform spherical morphology, high colloidal stability, efficient drug encapsulation, and sustained biphasic drug release consistent with a core–shell diffusion mechanism. In LN229 glioblastoma cells, folic acid conjugation significantly enhanced cellular internalisation and cytotoxic efficacy compared to free drugs and non-targeted nanoparticles. Combination index analysis revealed strong synergism between TMZ and ellagic acid, resulting in markedly reduced IC₅₀ values. Mechanistic studies demonstrated apoptosis induction, increased DNA damage, inhibition of cell migration at sub-cytotoxic concentrations, and downregulation of PARP gene expression. Conclusion: Overall, this study establishes a targeted core–shell nanotherapeutic strategy that integrates chemotherapy with DNA repair inhibition to overcome TMZ resistance, offering a mechanistically sound strategy that serves as a foundational framework for future translational research. Full article

Depression is one of the most common mental disorders in modern society, and it has become a serious threat to human health. The limitations of existing antidepressant drugs have prompted people to turn to the multi-target, low-toxic side effects of natural products. This article reviews the conventional nutrients (omega-3 fatty acids, folic acid, and mineral elements) and functional active ingredients (flavonoids, polysaccharides, saponins, and terpenoids) in medicinal and food homologous substances (MFHs). They show antidepressant potential by regulating neurotransmitters, improving hypothalamic–pituitary–adrenal (HPA) axis function, promoting neuroplasticity, inhibiting neuroinflammation, regulating ferroptosis, and interfering with the gut–brain axis. In addition, this paper discusses the application prospects of modern technologies such as microbial fermentation and nano-delivery in improving the bioavailability of MFHs and product development. In summary, MFHs have potential application value in dietary intervention and adjuvant therapies for depression; in the future, randomized controlled clinical trials should be strengthened, and multi-omics technology should be combined to promote the development of precision products so as to provide a new perspective for the development of new antidepressant drugs. Full article

Halloysite nanotubes (HNTs), composed of an aluminosilicate framework, are naturally abundant, biocompatible, and sustainable clay minerals with a tubular morphology and tunable surface chemistry, making them attractive platforms for targeted, multifunctional drug delivery systems. In this study, a zinc ferrite integrated halloysite nanocomposite (ZnFe₂O₄/HNT) was developed via a one-pot synthesis approach for sustained release of cisplatin (Cp), aiming to reduce systemic toxicity and enhance cell-specific activity. The nanocomposites were further functionalized by integrating Cp (Cp: ZnFe₂O₄/HNT ratio 0.05) and folic acid (ZnFe₂O₄/HNT/Cp: FA ratio 0.05), followed by PEGylation (0.17 µL/mg of ZnFe₂O₄/HNT/Cp/FA/PEG). The structural and surface characteristics, phase, interfacial interactions (FA and Cp), and colloidal stability of nanoformulations were systematically investigated using powder X-ray diffraction analysis (XRD), Fourier transformed infrared (FT-IR) spectroscopy, zeta potential analysis, scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS), high-resolution transmission electron microscopy (HRTEM), and diffuse reflectance UV–visible (DRS-UV-Vis) spectroscopy. The results confirmed that ZnFe₂O₄ integration preserved the clay’s tubular framework while inducing nanocrystallization of both ferrite and cisplatin, indicating molecular dispersion within the clay matrix. Functionalization with FA (ZnFe₂O₄/HNT/Cp/FA) promoted amide bond linkage, modulated Cp-FA interactions, and significantly enhanced cumulative Cp release compared to the non-functionalized system ZnFe₂O₄/HNT/Cp (10.3% at 72 h vs. 34.4% at 72 h) under tumor acidic conditions (pH 6.6). PEGylation maintained the controlled release profile while improving dispersion stability. In vitro cytotoxicity studies revealed that FA-conjugated nanocomposites exhibited enhanced, time-dependent anticancer activity against HeLa cervical cancer cells, with reduced toxicity toward normal fibroblasts, indicating preferential cellular uptake via folate receptor-mediated mechanism. Overall, this work demonstrates that FA-functionalized ZnFe₂O₄/HNT nanocomposite provides an effective clay-based platform for modulating Cp release and enhancing folate receptor protein-mediated targeted therapy for cervical cancer. Full article

Background/Objectives: Heart transplant recipients are particularly at risk for micronutrient deficiencies due to chronic immunosuppression, metabolic disorders, gastrointestinal absorption disorders, and increased postoperative demand. Despite a growing body of evidence suggesting their clinical relevance, the prevalence, characteristics, and consequences of these deficiencies remain poorly defined. The aim of this review was to assess of selected micronutrient deficiencies in personnel after heart vaccination and risk factors for their control. Methods: This scoping review was conducted in accordance with the Joanna Briggs Institute’s scope review methodology and presented in accordance with the PRISMA-ScR guidelines. A systematic search of PubMed, Scopus, EBSCO, Web of Science, Google Scholar, and Cochrane Library (January–February 2026) identified studies assessing micronutrient deficiencies in adult heart transplant recipients. Original publications, meta-analyses, and reviews available in full text in English were eligible for the review. Data extraction was carried out independently by two reviewers; using the PCC (Population–Concept–Context) model. Results: Of the 35 pre-identified records, 12 studies met the inclusion criteria. The most commonly reported deficiencies included iron, vitamin D, and B vitamins, and their incidence varied widely due to heterogeneous diagnostic criteria. Iron deficiency—both absolute and functional—was common and often associated with inflammation and impaired hepcidin regulation. Vitamin D deficiency persisted before and after transplantation and was associated with impaired bone health, inflammation, and a potentially increased risk of infection. Elevated homocysteine levels associated with low levels of folic acid and vitamin B6 have been identified as potential contributing factors to atherosclerotic and thrombotic complications. Limited evidence also points to deficiencies in iodine, zinc, and other trace elements. Conclusions: Micronutrient deficiencies are common among heart transplant recipients and can adversely affect immune system function, cardiovascular risk, and overall clinical outcomes. Routine evaluation and targeted correction of deficiencies should be considered in post-transplant care. Further prospective, multicenter, and interventional studies are needed to establish standardized diagnostic criteria and evidence-based supplementation strategies. Full article

Background: Overactive bladder (OAB) is a common functional disorder in paediatric populations and is associated with significant psychological burden and impaired quality of life. Although oxybutynin is widely used as first-line pharmacological therapy, a substantial proportion of children exhibit incomplete symptom control or limited tolerability. Emerging evidence suggests that targeting metabolic dysfunction, oxidative stress, and neuromuscular excitability may provide additional therapeutic benefit. This retrospective observational study evaluated the clinical impact of an adjunctive nutraceutical formulation containing myo-inositol, microlipodispersed magnesium, folic acid, and vitamin C (LEVIGON™ PRO, Sanitpharma; Milan, Italy) in children with OAB receiving oxybutynin. Methods: Medical records of children diagnosed with OAB were retrospectively reviewed. After applying inclusion and exclusion criteria, 120 patients aged 5–15 years were included and allocated to two groups based on documented treatment: oxybutynin plus LEVIGON™ PRO (Group A, n = 60) or oxybutynin alone (Group B, n = 60). The primary outcome was complete daytime urinary continence at Day 112. Secondary outcomes included weekly incontinence episodes, voiding frequency, bladder wall thickness, uroflowmetry parameters, and Patient Perception of Bladder Condition (PPBC) scores. An exploratory subgroup analysis was performed in 34 children with impaired fasting glucose (ifg), assessing fasting glucose, insulin, and homa-ir. results: by day 112, complete daytime continence was achieved in 61.7% of patients in group a and 48.3% in group b (absolute risk difference 13.4%; nnt ≈ 7.5; p = 0.14). across secondary endpoints, the combination therapy group showed significantly greater longitudinal improvements (group × time interaction, p < 0.05), including reductions in weekly incontinence episodes, voiding frequency, post-void residual volume, and ppbc scores, as well as increases in mean voided volume, qmax, and reductions in bladder wall thickness. in the ifg subgroup, greater reductions in fasting glucose, fasting insulin, and homa-ir were observed in group a compared with group b (p < 0.01). Both treatments were well tolerated, with no serious adverse events reported. conclusions: adjunctive nutraceutical therapy combined with oxybutynin was associated with greater improvements in several clinically relevant secondary outcomes in children with OAB, with a favourable tolerability profile. Although the primary endpoint did not reach statistical significance, the overall pattern of findings may suggest a possible additive benefit; however, these findings may be influenced by residual confounding inherent to the retrospective observational design. Therefore, the results should be considered hypothesis generating and require confirmation in prospective randomized controlled trials. Full article

With increasing environmental pollution and a high incidence of respiratory infections, pulmonary nodules (PN) are being detected more frequently. Although most are benign, they are often accompanied by chronic inflammation and localized fibrosis, which may predispose patients to progression toward idiopathic pulmonary fibrosis (IPF). However, the biological relationship between benign pulmonary nodules (BPNs) and IPF remains poorly understood. Therefore, this study aims to investigate the shared molecular mechanisms and identify potential biomarkers linking BPN and IPF, with the goal of elucidating the pathogenic transition from BPN to IPF. In this study, microarray data from GEO datasets were systematically analyzed to explore shared molecular mechanisms, immune infiltration characteristics, and potential early intervention strategies linking BPN and IPF. Differential expression analysis, protein–protein interaction (PPI) networks, weighted gene co-expression network analysis (WGCNA), and integrative machine learning approaches identified MME and ANKRD23 as key hub genes associated with the transition from BPN to IPF. Both genes demonstrated strong diagnostic performance, with Area Under the Curve (AUC) values exceeding 0.7, and were significantly correlated with immune cell infiltration, particularly effector memory CD8⁺ T cells. Functional enrichment and gene set enrichment analyses indicated that these genes were mainly involved in immune-related processes in BPN, while in IPF, ANKRD23 was linked to cytoskeletal organization and genomic stability, and MME was enriched in profibrotic pathways such as TGF-β signaling. The diagnostic value of these biomarkers was further validated in a bleomycin-induced IPF mouse model using quantitative polymerase chain reaction (qPCR). In addition, drug–gene interaction prediction and molecular docking analyses highlighted several naturally derived compounds with favorable binding affinity and anti-inflammatory properties, among which folic acid, curcumin, and arbutin emerged as promising candidates for safe early intervention. Collectively, these findings identify MME and ANKRD23 as potential biomarkers for early identification of BPN patients at risk of developing IPF and provide a theoretical basis for early diagnosis and targeted preventive strategies. Full article

Background: Cancer is a major health concern that significantly impacts the global population. Selective chemotherapeutic delivery is needed to improve the efficacy of cancer therapy while minimizing side effects in healthy cells. This study investigated the potential of gold nanoclusters (AuNCs) functionalized with poly(amidoamine) dendrimers (PAMAM) and folic acid (FA) to selectively deliver doxorubicin (DOX) to cancer cells that express the folate receptor (FR). Methods: AuNC synthesis was confirmed via UV–visible and Fourier transform infrared spectroscopy, nanoparticle tracking analysis, and transmission electron microscopy. Folic acid (FA) was incorporated for cell surface receptor targeting, while the triphenylphosphonium cation (TPP⁺) was added to improve mitochondrial localization. Cytotoxicity (MTT), apoptosis, caspase 3/7, mitopotential, and oxidative stress assays were assessed using human MCF-7 (breast adenocarcinoma), HeLa (cervical carcinoma), Caco-2 (colon adenocarcinoma), MDA-MB-231 (epithelial breast cancer), and the embryonic kidney (HEK293) cells. Results: Favorable DOX loading (>78%), with more than 90% of the drug released at pH 4.5, was achieved. A dose-dependent increase in cytotoxicity was observed, with IC50 values lower in cancer cells than HEK293 cells, indicating selective toxicity and minimal off-target effects. Targeting nanocomplexes produced the best responses in the mitopotential, caspase, and oxidative stress assays in HeLa and MCF-7 cells. Conclusions: The improved cytotoxicity in cancer cells may be due to folate-receptor-mediated cellular uptake, as well as the mitochondrial uptake of TPP⁺ nanocomplexes. This highlighted the potential of the drug–AuNC nanocomplexes to limit systemic side effects, proposing a potential novel strategy for drug delivery to cancer cells. Full article

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with a five-year survival rate of only 26%, primarily due to late-stage diagnosis and limited treatment options. Exosomes, nanosized extracellular vesicles released by nearly all cell types, have emerged as promising tools in both diagnostics and therapeutics. Their unique composition containing proteins, lipids, and nucleic acids reflects the molecular profile of their cell of origin, making them excellent candidates for non-invasive early detection biomarkers. For therapeutic applications, exosomes offer biocompatible, low-immunogenicity platforms capable of delivering diverse therapeutic agents, including small molecules, siRNAs, and antimetabolites, directly to tumor cells while minimizing systemic toxicity. Functionalization strategies, such as folic acid tagging, have further enhanced tumor specificity, especially in cancers with high folate receptors. However, clinical translation is hindered by challenges including lack of standardized isolation and characterization methods, high production costs, and regulatory uncertainties. Despite these limitations, ongoing research continues to optimize exosome production, targeting, and integration with conventional therapies. Milk- and colostrum-derived exosomes have shown promising potential due to their abundance, scalability, oral bioavailability, and safety. Collectively, exosomes represent a transformative approach in lung cancer management, with the potential to improve early diagnosis, enhance therapeutic efficacy, and reduce adverse effects, thereby offering a path toward more personalized and effective cancer care. Full article

Background: Co-delivery of two drugs with diverse physicochemical properties and a specific administration sequence holds great importance in cancer theranostics to overcome drug resistance and reduce side effects. Paclitaxel (PTX) and hydroxycamptothecin (HCPT) have long been used clinically as chemotherapeutic agents for Nasopharyn-geal carcinoma (NPC). However, their clinical application is severely restricted by low water solubility, poor stability, and systemic adverse reactions. Nanoparticle-based drug delivery systems provide a promising platform for combination cancer therapy. Methods: In this study, folic acid-modified and dual drug-loaded self-assembled HCPT/PTX@FA@p-PS-SPIONs were successfully fabricated via the emulsification–solvent evaporation method using amphiphilic phosphorylated polystyrene (p-PS). The characterization, cellular uptake, and in vivo pharmacokinetic profiles of the nanoparticles in NPC models were systematically investigated. Result: HCPT/PTX@FA@p-PS-SPIONs were successfully prepared with p-PS as the copolymer backbone. The nanoparticles exhibited a uniform particle size of 196.9 ± 5.5 nm and a zeta potential of −7.3 ± 0.7 mV. The encapsulation efficiency (EE) was 81.4 ± 2.5% for PTX and 67.6 ± 4.1% for HCPT. The drug loading (DL) efficiency was 18.4 ± 1.5% for PTX and 12.2 ± 1.0% for HCPT. HCPT/PTX@FA@p-PS-SPIONs showed favorable biocompatibility. Sustained and sequential release of the two drugs contributed to an enhanced therapeutic effect. Moreover, under magnetic field (MF) guidance, HCPT/PTX@FA@p-PS-SPIONs exhibited stronger inhibitory effects on NPC cells than single-drug, cocktail, or dual-drug groups, demonstrating the superiority of the combined therapy. Pharmacokinetic studies in rats revealed that the half-lives of PTX and HCPT were 3.9 ± 1.2 h and 4.7 ± 1.1 h, respectively, confirming that HCPT/PTX@FA@p-PS-SPIONs could resist rapid metabolism and clearance in vivo. Conclusions: The long-circulating, folic acid-targeted nanoparticles HCPT/PTX@FA@p-PS-SPIONs show great potential for the targeted therapy of nasopharyngeal carcinoma. Full article

Background: Liver cancer is a complex malignant tumor; gambogic acid (GA) has significant anti-cancer potential, but poor water solubility and low bioavailability limit its clinical application. In this paper, by integrating nanocrystal (NC) technology and an active targeting strategy, a new nanoagent—folic acid-modified phospholipid–gambogic acid nanocrystals (GA-NCs@FA)—was developed to improve the delivery efficiency and therapeutic effect of GA in the treatment of liver cancer. Methods: GA-NCs@FA was prepared by the CO₂-assisted precipitation method and the thin-film hydration method. The in vitro anti-tumor activity of GA-NCs@FA was evaluated by cytotoxicity, as well as a scratch and uptake test. A HepG2 tumor-bearing nude mouse model was established to investigate the in vivo distribution and tumor targeting of GA. The in vivo anti-tumor activity was evaluated by the tumor inhibition rate, and the pathological changes of organs in each group were observed by H&E staining. Results: GA-NCs@FA significantly reduced HepG2 cell viability (IC₅₀: 0.50 μg·mL⁻¹) and migration ability (48 h healing rate: 11.50%) and enhanced intracellular fluorescence intensity. In vivo analysis showed that GA-NCs@FA significantly increased the accumulation of drugs in tumor tissues by active targeting and achieved a tumor growth inhibition rate of 70.9%. Histopathology confirmed that GA-NCs@FA induced the most obvious nuclear pyknosis and necrosis in tumor tissues while maintaining good biosafety. Conclusions: GA-NCs@FA significantly prolongs the systemic circulation time of the drug and enhances intratumoral accumulation; therefore, it is a method that can be considered for active targeting and treatment of liver cancer. Full article

Objectives: To summarize the best evidence regarding folic acid supplementation for preventing neural tube defects (NTDs) in women of childbearing age and to develop a structured evidence summary for guiding clinical practice. Methods: We systematically searched multiple databases and professional websites from 1 January 2013 to 18 September 2025. Sources included 7 databases and 20 professional websites. The search targeted clinical guidelines, expert consensuses, best practices, and recommended practices on folic acid supplementation for NTD prevention in women of childbearing age. The retrieved literature underwent quality assessment, evidence extraction, and summarization. Results: The review included 17 publications: 10 guidelines, 4 expert consensuses, 2 recommended practices, and 1 best practice. From these, 14 distinct evidence statements were synthesized and organized into five thematic dimensions: risks of neural tube defects and the role of folic acid, time window of neural tube closure, timing and dosage of folic acid supplementation, relationship between dietary folic acid and folic acid tablets, and folic acid-related testing. The key recommendations include initiating supplementation at least 3 months preconception, with daily doses of 0.4 mg for low-risk, 1.0 mg for moderate-risk, and 4.0–5.0 mg for high-risk women, continuing through the first trimester, emphasizing that dietary intake alone is insufficient, and advising against routine folate testing. Conclusions: This study synthesized the best available evidence regarding folic acid supplementation for preventing NTDs in women of childbearing age, providing an evidence-based foundation to inform clinical practice, particularly for healthcare systems and populations in regions without mandatory folic acid food fortification. Full article

The inadequate biosafety of MRI contrast agents (CAs) remains a challenging issue. Both increasing the magnetic relaxivity of CAs and targeting them through conjugation with folates are promising approaches to addressing this issue. Silica nanoparticles (SNs) with Mn²⁺ ions specifically localized in the outer layer were selected as the target for further surface modification for the covalent attachment of folates. It was shown that when Mn-containing SNs are conjugated with folates via preliminary amino modification of the surface silanol groups, the folate-conjugated SNs suffer from colloidal instability. Thus, precoating Mn-containing SNs with unfolded BSA exposes surface amino groups that successfully conjugate with folates without loss of colloidal stability. Partial washout of surface-localized Mn²⁺ follows folate conjugation of Mn-containing SNs, although residual Mn²⁺ ions provide r₁₍₂₎ relaxivities of 62.1 (160.4) mM⁻¹s⁻¹ at 0.47 T. Full article