Search Results (458)

Glycosylation is the most common post-translational modification in the human proteome, with over half of all human proteins bearing covalently attached glycans. These glycan structures direct protein folding through ER quality control machinery, shield polypeptides from proteolytic degradation, regulate circulatory half-life via the asialoglycoprotein receptor, and serve as molecular signals for immune recognition and intracellular trafficking. For biopharmaceuticals, which constitute a rapidly growing share of approved drugs, glycan profiles are critical quality attributes that directly determine clinical efficacy and safety. Yet achieving the correct glycosylation on a therapeutic protein remains one of the field’s central challenges, as glycan biosynthesis is non-template-driven and highly sensitive to expression system and manufacturing conditions. This review connects the biological functions of glycosylation to the practical strategies of glycoengineering, examining how sequence design, expression system selection, and downstream enzymatic remodeling are used to optimize therapeutic glycoproteins. Clinical case studies spanning monoclonal antibodies, cytokines, and enzyme replacement therapies illustrate how glycan engineering translates into improved patient outcomes. We conclude by surveying emerging technologies poised to make precisely glycosylated therapeutics more accessible. Full article

Beyond their established role in lipid digestion, bile acids function as key metabolic and immune signaling molecules. This review synthesizes recent advances in bile acid metabolism within the context of gout and hyperuricemia, proposing a gut–liver–joint crosstalk framework. Dysregulated bile acid metabolism—characterized by a reduced total bile acid pool, decreased hydrophobic secondary bile acids, elevated 12α-hydroxy bile acids, and impaired enterohepatic circulation—has been mechanistically linked to both hepatic urate overproduction via the PPAR-α/xanthine oxidase pathway and monosodium urate crystal-induced NLRP3 inflammasome activation, although human causal evidence remains to be established. The nuclear receptor FXR suppresses NLRP3 at the transcriptional level, while the membrane receptor TGR5 acts post-translationally through Cyclic adenosine monophosphate/Protein Kinase A (cAMP/PKA) and Glucagon-like peptide-1 (GLP-1) signaling. Gut microbiota dysbiosis amplifies these abnormalities through a vicious cycle of reduced bile acid signaling, increased intestinal permeability, and systemic endotoxemia. Based on these insights, we summarize five therapeutic strategies: FXR modulators, TGR5 agonists, microbiota-based interventions, natural products, and ursodeoxycholic acid replacement therapy. Future research should prioritize gout-specific preclinical models, clinical trials of TGR5 agonists, standardized microbiota-based therapies, dual-target molecules, and personalized patient stratification based on bile acid profiles. Full article

Background and Clinical Significance: Hyperviscosity syndrome (HVS) is a rare complication of primary Sjögren’s syndrome (pSS). While therapeutic plasma exchange (TPE) is the standard treatment to clear pathogenic immunoglobulins, its execution can trigger severe, atypical systemic risks. Case Presentation: A 60-year-old woman with pSS and extreme polyclonal hypergammaglobulinemia (total protein 100 g/L, IgM 41 g/L) presented with an acute hyperviscosity crisis, causing retinopathy, neurological deficits, and skin ischemia. Emergency TPE with 5% albumin replacement successfully reduced IgM by ~90% (to 6.39 g/L), resolving HVS symptoms. However, 20 min post-procedure, the patient suffered sudden hemodynamic collapse (BP 50/30 mmHg) and developed multiple massive, expanding soft-tissue hematomas. Laboratory tests revealed a coagulopathy consistent with plasma protein depletion following therapeutic plasma exchange, characterized by severe hypofibrinogenemia (1.35 g/L) and a 50% reduction in total serum protein. TPE was permanently discontinued. The patient was successfully stabilized using aggressive fluid resuscitation, vasopressors, and fresh frozen plasma (FFP) transfusions, followed by maintenance therapy with rituximab. Conclusions: In conclusion, clinicians should remain vigilant that severe hyperviscosity syndrome can be driven by a polyclonal increase in immunoglobulins rather than just monoclonal entities; furthermore, managing this condition requires careful balancing of TPE efficacy against its potential to trigger profound depletion coagulopathy. Full article

The Kidney Disease: Improving Global Outcomes (KDIGO) CGA framework remains the essential basis for chronic kidney disease (CKD) classification, risk stratification, and guideline-based therapy. However, eGFR and albuminuria do not always explain the physiological mechanism maintaining the current filtration level or the heterogeneity of treatment responses. This narrative review proposes a hypothesis-generating functional–hemodynamic extension of KDIGO CGA that incorporates renal functional reserve (RFR), blood pressure, volume status, proteinuria phenotype, and selected tubular markers. RFR is discussed as a dynamic stress test of nephron reserve rather than as a replacement for eGFR or albuminuria. A low, zero, or negative RFR may suggest reserve exhaustion or relative hyperfiltration, but its interpretation depends on standardized testing conditions and clinical context. We distinguish established evidence-based therapy—RAAS blockade in albuminuric or hypertensive CKD, SGLT2 inhibition for kidney and cardiorenal protection, and non-steroidal MRA therapy in selected patients—from conceptual sequencing hypotheses such as RAASi-prioritized, SGLT2i-prioritized, early dual, or staged triple renoprotection. The review also summarizes albuminuria as a two-compartment phenomenon involving both glomerular passage and proximal tubular handling of filtered proteins. The proposed framework is not a validated treatment algorithm. It is intended to support physiological phenotyping, interpretation of early eGFR changes, and the design of prospective studies that test whether RFR adds independent prognostic or therapeutic value beyond KDIGO CGA. Full article

This paper presents the development, fabrication, and characterization of a droplet-based microfluidic platform designed for precise local thermal treatment of cancer cells, with prospective chemical targeting as a future application. The workflow begins with a finite element model (FEM) using COMSOL Multiphysics 6.0 to characterize coupled hydrodynamic and thermal behavior, specifically analyzing temperature distributions across single-phase and three-phase regimes. Following the simulation, work has progressed to the fabrication of a microfluidic device and the characterization of its platinum heat source and temperature detector to ensure precise thermal control. To replicate realistic biochemical conditions, experiments have employed a three-phase configuration of oil, water, and fluorescent BSA solution. In the final stage, DX5-GFP MES-SA cancer cells have replaced the BSA solution to complete the measurements. To ensure reagent homogenization and consistent cellular exposure, a serpentine channel design was utilized to induce Dean vortices, which significantly enhanced internal mixing within the droplets. Fluorescence-loss experiments demonstrated that localized heating above ~60 °C induces irreversible thermal damage in both model proteins (fluorescent BSA) and cancer cells, establishing a proof-of-concept basis for precise thermal regulation at the single-droplet level. By deactivating specific thermo-sensitive proteins responsible for drug resistance, this integrated approach to thermal and hydrodynamic optimization enhances the efficacy of chemical stimuli and provides a robust platform for investigating the modulation of cellular defense mechanisms in future biotechnological applications. The platform holds significant potential for advancing precision oncology by enabling systematic, single-cell-level investigation of heat-shock-mediated drug sensitization, with long-term implications for overcoming multidrug resistance in aggressive cancer therapies. Full article

The increased global prevalence of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic relapsing inflammatory condition of the gastrointestinal tract that creates a substantial socioeconomic burden. Existing pharmacotherapeutic treatments primarily target inflammatory signaling cascades and have disadvantages because of the side effects of drugs, reduced long-term efficacy, and high cost, necessitating the development of safe and sustainable adjunctive therapies. This review synthesizes mechanistic advances regarding dietary polysaccharides as bioactive agents that may have the capacity to induce remodeling of inflamed gastrointestinal tract in colitis and could be an adjunctive strategy as functional food ingredients due to their various biological activities in the management of colitis. Polysaccharides alleviate colitis through several interconnected pathways. First, they correct the gut dysbiosis by enriching beneficial taxa such as Lactobacillus, Bifidobacterium, and Akkermansia muciniphila. Second, fermentation of polysaccharides produces short-chain fatty acids (SCFAs), particularly butyrate, which serve as the primary energy source for colonocytes. Third, they restore intestinal barrier integrity by upregulating tight junction proteins such as ZO-1, occludin, and claudin, also performing pro-inflammatory cascade inhibition and elimination of oxidative stress via Nrf2/HO-1 activation The relationship between structural properties of polysaccharides based on molecular weight, monosaccharide composition, and biological functions of chemically modified dietary polysaccharides in colitis is studied. Dietary polysaccharides are explored here not as replacements for pharmacotherapy but as potential adjunctive or functional food-based interventions that may complement existing treatments as safe, multitargeted, and cost-effective interventions in prevention or long-term management of colitis and IBD. This review presents dietary polysaccharides function not as passive dietary fibers but as bioactive, multi-targeted, structurally dependent agents capable of restoring intestinal homeostasis, suggesting them as potentially safe, adjunctive interventions. Full article

RPE65, an isomerohydrolase expressed in retinal pigment epithelium (RPE), is critical for the visual cycle. More than 115 missense variants of the RPE65 gene have been associated with Leber’s congenital amaurosis (LCA), a severe childhood retinal dystrophy. Due to high genetic heterogeneity, the variant-specific pathogenic mechanisms remain largely uncharacterized. In this study we focus on an LCA patient carrying compound heterozygous RPE65 variants (c.200T > G, c.430T > C), aiming to dissect the mechanistic/functional basis of mutated protein-driven retinal degeneration and evaluate gene therapy-mediated restoration using patient-specific hiPSCs-RPE (iRPE). Transient overexpression of wild-type/mutant RPE65 in HEK293T cells showed both variants markedly destabilize the RPE65 protein through the autophagosome–lysosome degradation pathway and its isomerohydrolase activity required for the retinoid visual cycle. We further established a patient-specific iRPE platform suitable for enzymatic activity analysis. Characterization of patient-specific iRPE cells revealed those compound heterozygous variants did not compromise iRPE morphology, most gene expression, or core canonical physiological features of iRPE. However, they significantly downregulate endogenous RPE65 protein abundance and dampen enzymatic function. Subsequently, we delivered RPE65 via adeno-associated viral (AAV) vectors driven by either the ubiquitous CMV promoter or RPE-specific VMD2 promoter into patient iRPE to validate therapeutic potency, and verified that exogenous RPE65 supplementation effectively restores deficient isomerohydrolase activity in this disease model. Collectively, this work elucidates the variant-specific pathogenesis of RPE65-associated LCA and preliminarily assesses the efficacy of gene augmentation, providing preclinical experimental evidence to support the referral of this patient for clinical RPE65 gene replacement therapy. Full article

Background: In elderly patients with hypoalbuminaemia, hypoproteinaemia and advanced-stage PUs, chronic inflammation and wound-related protein loss contribute to a self-perpetuating circulus vitiosus, in which protein depletion drives deterioration of tissue repair processes, and in turn, ongoing wound-related catabolism further amplifies systemic protein loss. In this context, reduced serum albumin and total protein represent integrated indicators of systemic inflammatory and catabolic burden associated with delayed wound healing. Aim: This study evaluated the association between individualized nutritional replacement therapy and pressure ulcer healing in malnourished geriatric and palliative patients, using serum albumin, total protein, and PUSH score as longitudinal outcome indicators. Methods: A total of 78 malnourished geriatric and palliative patients with PUs, multiple comorbidities, and poor nutritional status (hypoalbuminemia and/or hypoproteinaemia) receiving patient-tailored nutritional replacement therapy participated in this study. PU assessment using the PUSH version 3.0 tool, as well as measurements of serum albumin and total protein concentrations, were performed on days 0, 30, 60, and 90. Results: Our study demonstrates significant improvement in the serum albumin levels, from 30.2 ± 6.19 at baseline to 42.1 ± 5.59 at day 90. Similarly, total protein concentrations increased from 57.8 ± 9.66 at baseline to 70.6 ± 7.03 at day 90. The improvement in protein status was accompanied by a significant reduction in the PUSH score, from 10.9 ± 2.94 at the first assessment to 2.9 ± 2.63 at the final assessment. Spearman’s rank-order correlation analysis between serum albumin, total protein, and PUSH score demonstrated a significant moderate inverse correlation at later assessment points (day 60 and 90). Conclusions: Individualized and targeted replacement therapy was associated with improved protein status and reduced pressure ulcer severity. Increases in serum albumin and total protein paralleled a marked reduction in PUSH scores, suggesting attenuation of the inflammatory-catabolic circulus vitiosus and a progressive shift toward wound healing in geriatric and palliative patients. Full article

Objectives: To present novel strategies in the diagnosis and management of spondylodiscitis in a patient with tetraplegia. Case Presentation: A 44-year-old man presented with increased spasms despite having a SynchroMed II Medtronic for intrathecal infusion of baclofen. The C-reactive protein level was raised. Infection was suspected, but there were no localising signs. Positron Emission Tomography (PET) was performed to identify the focus of infection. PET showed an increased Fluorodeoxyglucose uptake in the L-5 vertebral body and the associated ill-defined soft tissue anteriorly. There was significant erosion and destruction of the S-1 vertebra. Magnetic Resonance Imaging of the lumbo-sacral spine revealed destruction and collapse of the S-1 vertebral body and a 6 cm × 2 cm anterior paravertebral abscess collection. This patient was managed in his home. Intravenous administration of 1 g of Ertapenem daily was provided by community nurses for eight weeks. Blood tests were performed in the community setting, and the patient was monitored by spinal unit doctors. Results: Follow-up CT revealed abnormal soft tissue, expanding and replacing the S-1 vertebral body, with appearances in keeping with an infective process. Using CT guidance and the Madison bone biopsy kit, multiple cores were obtained from the left sacral bone. Four of the five specimens showed no growth after extended incubation. Propionibacterium acnes were isolated after 10 days of incubation from the tissue from the sacral bone biopsy only. A shared decision was made towards active surveillance. Follow-up CT of the abdomen showed a stable appearance of the lumbar and sacral spine. Conclusions: A complex case of spondylodiscitis can be diagnosed and managed while the patient stays mainly in their home, avoiding prolonged admission to the spinal unit, in alignment with the “hospital to community” aspect of the National Health Service’s 10-year Health Plan for England. A diagnostic pathway with PET-CT as the first approach proved useful when the site of infection was unclear. Active surveillance obviated the need for extended periods of antibiotic therapy, which could have led to complications such as antibiotic-induced toxicity and microbial resistance to antibiotics. Full article

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of oncology but are increasingly associated with cardiovascular immune-related adverse events (irAEs), including myocarditis, heart failure, arrhythmias, and vascular complications. Among these, ICI-associated myocarditis represents the most severe manifestation, often characterized by high mortality and challenging early diagnosis. Detecting subclinical myocardial injury before irreversible cardiomyocyte necrosis occurs remains a major unmet need in contemporary cardio-oncology. This narrative expert review critically examines the biological rationale, preclinical evidence, and emerging clinical data supporting the potential role of heart-type fatty acid-binding protein (H-FABP) as an adjunctive biomarker of early immune-mediated myocardial injury during ICI therapy. H-FABP is a small cytosolic lipid chaperone abundantly expressed in cardiomyocytes and rapidly released into the circulation following subtle membrane destabilization and metabolic stress, frequently preceding detectable troponin elevation in other forms of myocardial injury. Experimental studies support a mechanistic association between H-FABP release, inflammasome activation, cytokine amplification, mitochondrial dysfunction, and immune–metabolic cardiomyocyte stress. Preliminary clinical observations further suggest that H-FABP elevations may occur during ICI treatment even in the absence of overt myocarditis or concomitant increases in high-sensitivity cardiac troponins (hs-cTns). Although H-FABP cannot replace hs-cTn, which remains the cornerstone biomarker for the diagnosis of clinically significant ICI-associated myocarditis, its rapid kinetics and sensitivity to early metabolic membrane injury support its potential role as an investigational adjunctive biomarker for early surveillance and risk stratification. This approach may be particularly relevant in patients receiving high-risk combination ICI regimens or in individuals with pre-existing cardiovascular disease. However, current evidence remains limited, and large prospective multicenter studies integrating H-FABP with hs-cTns, natriuretic peptides, cardiac magnetic resonance imaging, and clinical outcomes are required before routine clinical implementation can be considered. Full article

Gaucher disease is a prototypical lysosomal sphingolipid storage disorder caused by pathogenic variants in GBA1, resulting in glucocerebrosidase deficiency and accumulation of bioactive lipids, including glucosylceramide and glucosylsphingosine (lyso-Gb1). While non-neuronopathic Gaucher disease is effectively managed with enzyme replacement and substrate reduction therapies, neuronopathic forms remain largely refractory to treatment due to progressive central nervous system (CNS) involvement and limited penetration of current therapies across the blood–brain barrier. Disease pathobiology extends beyond lysosomal substrate accumulation to encompass dysregulated sphingolipid signaling, particularly sphingosine-1-phosphate (S1P)-mediated “inside-out” signaling, alongside neuroinflammation, oxidative stress, and glial activation, which collectively drive neurodegeneration. In this review, we synthesize current knowledge on sphingolipid metabolism and signaling in neuronopathic Gaucher disease and integrate these mechanisms into a three-tier, CNS-focused biomarker framework. The first tier comprises substrate-proximal markers of lysosomal burden (lyso-Gb1), which reflect GCase deficiency and correlate with systemic disease severity but incompletely capture CNS pathology. The second tier comprises markers of glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], glycoprotein non-metastatic melanoma protein B [GPNMB]), which reflect the downstream neuroimmune response to sphingolipid accumulation. The third tier comprises markers of neuroaxonal injury (neurofilament light chain [NfL]), which index irreversible neuronal damage as the terminal consequence of uncontrolled CNS disease. Together, these tiers map distinct but mechanistically interconnected stages of disease progression, from lysosomal dysfunction through glial activation to neuroaxonal loss, enabling stage-specific interpretation of biomarker signals that single-analyte approaches cannot provide. We further examine how S1P-mediated inside-out signaling links intracellular lipid dysregulation to extracellular neuroimmune and neurovascular responses and how the blood–brain barrier shapes compartment-dependent biomarker behavior across cerebrospinal fluid and blood. By grounding biomarker selection in this mechanistic cascade, the framework provides explicit criteria for pairing analytes across tiers, interpreting discordance between peripheral and CNS compartments, and designing multi-modal endpoints for clinical trials of CNS-penetrant therapies. Despite these advances, significant challenges remain, including limited longitudinal datasets, variability in assay methodologies, and incomplete validation of biomarkers as surrogates of CNS disease progression. Addressing these gaps will require harmonized, multi-modal approaches integrating biochemical, functional, and imaging measures. By positioning neuronopathic Gaucher disease as a model of sphingolipid-driven neurodegeneration, this review highlights opportunities for biomarker-guided therapeutic development relevant to Gaucher disease and the broader spectrum of sphingolipid-associated neurological disorders. Full article

Background/Objectives:Helicobacter pylori infection is traditionally associated with gastrointestinal diseases; however, increasing evidence suggests that it may have systemic effects involving inflammatory, metabolic, and hematological pathways. Despite this, integrated evaluations of these domains remain limited, particularly in Middle Eastern populations. This study aimed to assess the impact of H. pylori infection on inflammatory, metabolic, and hematological parameters among adults. Methods: A case–control study was conducted including 100 participants (50 H. pylori-positive patients and 50 healthy controls) recruited from Qassim Health Cluster, Saudi Arabia. Demographic and clinical data were collected, and blood samples were analyzed for random blood sugar (RBS), glycated hemoglobin (HbA1c), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hemoglobin, ferritin, and white blood cell count (WBC). Statistical analyses included group comparisons, Spearman correlation, logistic regression, and receiver operating characteristic (ROC) curve analysis. Results: The infected group showed significantly higher levels of RBS and HbA1c, indicating impaired glycemic control. Inflammatory markers (CRP and ESR) were also significantly elevated compared to controls (p < 0.001). Hemoglobin and ferritin levels were significantly lower in the infected group (p < 0.001), suggesting disturbed iron metabolism. Correlation analysis revealed positive associations between inflammatory markers and glycemic indices, and negative associations with hemoglobin and ferritin. Multivariable logistic regression identified CRP (adjusted OR = 1.33, 95% CI: 1.04–1.71) and ESR (adjusted OR = 1.09, 95% CI: 1.02–1.16) as independent predictors of H. pylori infection after adjustment for smoking status and fast-food consumption. The combined model demonstrated acceptable discriminatory performance with an AUC of 0.82 (95% CI: 0.74–0.90). Conclusions:Helicobacter pylori infection was associated with significant inflammatory, metabolic, and hematological alterations, supporting its potential role as a systemic condition beyond the gastrointestinal tract. These associations remained significant after adjustment for major lifestyle-related confounders, including smoking status and fast-food consumption. Although the combined inflammatory model demonstrated acceptable discriminatory performance, it should currently be considered mainly for research or preliminary screening purposes and not as a replacement for established diagnostic methods for active H. pylori infection. Further large-scale longitudinal and interventional studies are warranted to clarify causality and evaluate the impact of eradication therapy on systemic outcomes. Full article

Cardiovascular and cerebrovascular diseases, encompassing cardiac arrhythmias, atherosclerosis, and ischaemic stroke, remain the foremost causes of death and long-term disability globally. Despite improved outcomes with conventional therapy, substantial residual risk persists, providing the impetus for gene-based intervention. KCNQ1/KCNH2 suppression-and-replacement, SCN5A base editing, and structural protein restoration via PKP2 and TMEM43 have each demonstrated capacity to re-establish electrophysiological stability in arrhythmia models. For atherosclerosis, RNA-based agents, notably inclisiran, alongside in vivo editing strategies such as VERVE-101, offer durable lipid reduction and attenuation of vascular inflammation. In ischaemic stroke, cGAS–STING silencing, AAV-NeuroD1-mediated neuronal reprogramming, and delivery of neurotrophic factors, including VEGF and BDNF, extend the therapeutic window well beyond reperfusion. Collectively, these approaches position gene therapy as a meaningful complement to standard care, capable of addressing root molecular pathology rather than downstream consequences. This review synthesises current mechanistic understanding, translational obstacles, and emerging directions across these three disease domains, arguing that, delivery and safety challenges notwithstanding, gene therapy stands to substantially reshape how cardiovascular and cerebrovascular diseases are prevented and treated. Full article

Background: Certain metabolites of the tryptophan-kynurenine (Trp-KYN) pathway, which are primarily cleared via tubular transport, have been linked to end-stage kidney disease (ESKD). Uromodulin—a protein expressed exclusively in the kidneys—is a key regulator of renal structure and function, as well as a direct marker of tubular health. This preliminary study explores the hypothesis that serum uromodulin correlates with Trp-KYN metabolites, potentially revealing new pathophysiological pathways in patients undergoing kidney replacement therapy (KRT). Given the link between serum uromodulin, Trp-KYN metabolites, and tubular function, we examined their correlation in KRT patients. Furthermore, we assessed how various clinical and dialysis parameters influence serum uromodulin levels. Methods: A total of 64 stable patients from a single dialysis center receiving hemodialysis (HD) or hemodiafiltration (HDF) were enrolled. Pre- and post-dialysis concentrations of uromodulin, Trp, KYN, kynurenic acid (KYNA), 3-hydroxykynurenine (3-OHKYN), and their reduction ratios (RRs) were established. High-performance liquid chromatography (HPLC) was used to estimate the KYN pathway metabolite levels, whereas uromodulin concentration was measured using an immunoenzymatic assay. Results: Detectable serum uromodulin was found in only 30 patients. This group was predominantly male (p < 0.001) and characterized by shorter dialysis vintage (p < 0.001), a higher prevalence of residual kidney function (RKF) (p = 0.001) and diabetes mellitus (p = 0.028), higher pre-dialysis serum phosphorus levels (p = 0.015), and more frequent use of loop diuretics (p = 0.004). Furthermore, univariate analysis revealed significantly higher pre-dialysis (p = 0.004) and post-dialysis (p = 0.025) serum Trp concentrations in the uromodulin-positive group. Pre-dialysis serum uromodulin concentration correlated positively with pre-dialysis Trp level (p < 0.001) and negatively with the pre-dialysis KYN/Trp ratio (p = 0.008), but not with other metabolites that are also subject to tubular transport mechanisms. Post-dialysis uromodulin levels correlated positively only with post-dialysis Trp level (p = 0.005). Patients treated with HDF had significantly higher RR for uromodulin than those treated with HD (p = 0.01). Conclusions: The presented data indicate that serum uromodulin levels are correlated with RKF. Additionally, the presence of detectable serum uromodulin may indicate reduced immunological activation, leading to diminished activity within the Trp-KYN pathway. Full article

Chronic liver disease remains a major global health burden, with liver transplantation as the only definitive therapy despite severe limitations in donor availability, surgical morbidity, and patient eligibility. Although the liver has substantial intrinsic regenerative capacity, endogenous repair is often insufficient in chronic injury, cirrhosis, and acute-on-chronic liver failure. As a result, regenerative strategies that restore liver function without whole-organ replacement are increasingly pursued. This review examines controlled release biomaterial-based liver regeneration platforms, particularly those that utilize hydrogels and/or complementary nanoparticle systems, as clinically practical tools to enhance endogenous regeneration. We include discussion of both 3D scaffold-based and injectable hydrogels to enhance regeneration. Used as biological support and controlled release mixtures, they enable local retention, entrapping and controlling the release of regenerative cues including growth factors (HGF, EGF, etc.), nucleic acids for gene expression, stem cells or other cell populations, and conditioned extracellular vesicles, overcoming poor cell engraftment, short cytokine half-lives, and other limitations. Further, synthetic nanoparticles can structure release at the protein/molecular level as well as catalytically modulating oxidative stress and inflammation. Within the context of these systems, we structure the anatomical, engineering, and imaging considerations essential for the clinical translation of gel composite systems while highlighting remaining barriers to wider clinical adoption. Collectively, these advances position biomaterial-enabled regenerative therapies as a realistic alternative or bridge to donor restricted liver transplantation. Full article