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GLP-1R-GIPR-PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice.
Nature
Daniela Liskiewicz, Aaron Novikoff, Ahmed Khalil +50 more
There are increasing numbers of effective drugs to improve obesity-linked metabolic dysfunction; GLP-1R-GIPR co-agonism is effective in the management of obesity and type 2 diabetes1,2, and lanifibranor-a nuclear-acting small-molecule triple agonist of PPARα, PPARγ and PPARδ-is in clinical phase 3 trials for the treatment of metabolic dysfunction-associated steatohepatitis3. Here, seeking to further improve the metabolic efficacy of GLP-1R-GIPR co-agonism, we report the development of a unimolecular quintuple agonist that combines the body weight-reducing and blood glucose-lowering effects of GLP-1R-GIPR co-agonism with the insulin-sensitizing and anti-inflammatory effects of lanifibranor via its targeted delivery into GLP-1R- and GIPR-expressing cells. In vitro, GLP-1-GIP-lanifibranor is indistinguishable from GLP-1-GIP in relation to incretin receptor signalling and shows equal stimulation of insulin secretion in isolated mouse islets. In vivo, however, GLP-1-GIP-lanifibranor outperforms GLP-1R-GIPR co-agonism and semaglutide, further decreasing body weight, food intake and hyperglycaemia in obese and insulin-resistant mice through synergistic incretin and PPAR action. The metabolic action of GLP-1-GIP-lanifibranor is blunted in mice with genetic or pharmacological inhibition of GLP-1R, GIPR or PPARδ and is absent in DIO double incretin receptor-knockout mice, collectively suggesting that GLP-1-GIP-lanifibranor has substantial therapeutic value in the treatment of obesity and diabetes.
Impact of Tirzepatide on FIB-4 in Patients with Type 2 Diabetes: A Comparison between GLP-1RA-naïve and GLP-1RA Switch Initiation in a Retrospective Cohort.
Intern Med
Hiroyuki Ito, Chiaki I, Mizuki Matsushita +6 more
Objective Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to improve hepatic inflammation and steatosis in patients with type 2 diabetes. However, whether its effects on Fibrosis-4 (FIB-4), a surrogate marker of liver fibrosis, differ between patients naїve to GLP-1 receptor agonists (GLP-1RAs) and those who have switched from a GLP-1RA remains unclear. Methods In this single-center retrospective study, 65 Japanese patients with type 2 diabetes received tirzepatide for ≥6 months (GLP-1RA-naïve: n=15; GLP-1RA-treated: n=50). The primary outcome was change in the FIB-4. The secondary endpoints included changes in glycated hemoglobin (HbA1c), body weight, urinary protein, and estimated glomerular filtration rate (eGFR). Multivariable analyses were performed to identify the predictors of FIB-4 improvement. Results FIB-4 significantly decreased in the GLP-1RA-naïve group (from 1.55±1.01 to 1.25±0.74, Δ-0.26±0.32, p<0.01) but not in the GLP-1RA-treated group (Δ-0.02±0.23), with a significant between-group difference (p<0.05). HbA1c decreased in both groups, with a greater reduction in GLP-1RA-naïve patients (Δ-2.0±1.3% vs. -1.0±1.3%, p<0.01). Body weight decreased significantly in both groups (-3.5±5.5 kg vs. -2.2±3.5 kg), with no between-group difference. A multivariable analysis identified age, baseline FIB-4, and GLP-1RA-naïve status as independent predictors of FIB-4 reduction. Conclusion Tirzepatide significantly reduced FIB-4, particularly in patients who were GLP-1RA-naïve, and produced substantial reductions in HbA1c and body weight. As an exploratory and hypothesis-generating analysis, these findings suggest that initiating tirzepatide in GLP-1RA-naïve patients may be associated with favorable changes in fibrosis-related risk markers in patients with type 2 diabetes at a high risk of liver fibrosis.
Angiotensin-(1-7) suppresses pyroptosis in cerebral endothelium to decrease blood-brain barrier permeability and cognitive impairments in sepsis.
J Int Med Res
Yongli Han, Hongguang Ding, Yirun Chen +5 more
ObjectiveThis study aimed to explore the influence of the angiotensin-(1-7)/Mas receptor and angiotensin II/angiotensin II type 1 receptor pathways on pyroptosis during sepsis and their subsequent effects on cognitive function.MethodsAdult C57BL/6 mice were subjected to cecal ligation and puncture to induce sepsis. Brain microvascular endothelial cells were treated with angiotensin II and angiotensin-(1-7) to evaluate their impact on pyroptotic processes. Cognitive performance was assessed using the Morris water maze method, and blood-brain barrier permeability was quantified using Evans blue staining.ResultsCompared with the sham group, sepsis induced sustained activation of the angiotensin II/angiotensin II type 1 receptor pathway, whereas the angiotensin-(1-7)/Mas receptor pathway was progressively suppressed. Genetic ablation of cysteine-dependent aspartate protease-1 significantly attenuated pyroptosis in brain endothelial cells, decreased blood-brain barrier permeability, and enhanced cognitive function in septic mice compared with that in the cecal ligation and puncture group. Angiotensin-(1-7) treatment improved cognitive function in septic mice and significantly suppressed angiotensin II-induced pyroptosis, with these effects reversed by the Mas receptor antagonist A-779.ConclusionsThis study identified a novel mechanism in which angiotensin-(1-7) selectively suppresses angiotensin II-induced pyroptosis in brain endothelial cells, consequently ameliorating cognitive deficits during sepsis.
Euthyroid Sick Syndrome Precipitated By Rapid Weight Loss Following Semaglutide Initiation: A Case Report.
Clin Med Insights Endocrinol Diabetes
Ziad W Elmezayen, Farah Qrareya, Abdallah Abdallah +2 more
Euthyroid sick syndrome (ESS) is characterized by abnormal thyroid function tests, most notably a low triiodothyronine (T3) level, occurring in the absence of intrinsic thyroid disease. A 54-year-old woman presented to the endocrinology clinic with a 4-month history of progressive fatigue, lethargy, and new-onset cold intolerance after initiation of semaglutide for weight management. The dose was titrated monthly over 4 months, during which she experienced significant weight loss of 22 kg. Laboratory evaluation revealed a thyroid function profile classic for ESS, with low free T3, low-normal free T4, and a normal thyroid-stimulating hormone (TSH) level that was inappropriately low relative to the reduced T3. After exclusion of primary thyroid and pituitary disorders, a diagnosis of ESS secondary to the catabolic state induced by rapid weight loss was made. The patient was counseled that this represented a physiological adaptation rather than intrinsic thyroid disease. Semaglutide was continued given its metabolic benefits, and nutritional optimization with adequate caloric and protein intake was advised.
Indirect Comparative Efficacy and Safety of Tirzepatide Versus Oral Semaglutide for the Treatment of Overweight and Obesity.
Diabetes Obes Metab
Andreea Ciudin, Erin Johansson, Sarah Zimner-Rapuch +5 more
Tirzepatide, an injectable glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA), is approved for weight management in several regions. Oral GLP-1 RAs, such as semaglutide, are under investigation to improve convenience, acceptance and adherence versus injectable formulations. Currently, no studies have compared the efficacy and safety of tirzepatide with oral semaglutide for weight management. This study aimed to indirectly compare the efficacy and safety of weekly injectable tirzepatide 5, 10 and 15 mg for weight management in obesity and overweight versus daily oral semaglutide 50 mg.
THR-β Agonists vs Incretin Therapies for Noncirrhotic Metabolic Dysfunction-Associated Steatohepatitis (MASH): A Biopsy-Anchored Systematic Review With Grading of Recommendations Assessment, Development and Evaluation (GRADE) Certainty.
Cureus
Amirah A Alzaki, Mohammed Z Alqahtani, Eiman Aman +8 more
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease now targeted by new pharmacotherapies, including the thyroid hormone receptor beta (THR-β) agonist resmetirom, glucagon-like peptide-1 (GLP-1) receptor agonists (semaglutide, liraglutide), and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide. Each acts through distinct metabolic pathways, yet no head-to-head comparisons exist. The aim of this study was to systematically review randomized controlled trials assessing the efficacy and safety of resmetirom, GLP-1 receptor agonists, and dual GIP/GLP-1 receptor agonists in adults with biopsy-confirmed, non-cirrhotic MASH (F2-F3), and to evaluate the certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020, seven eligible randomized controlled trials (RCTs) involving 3,796 participants were identified through PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and trial registries (inception to October 2025). The comprehensive methodological protocol was filed in PROSPERO (reg. no. CRD420251230032) before the commencement of data collection. Data were extracted in duplicate; risk of bias was assessed using Cochrane Risk of Bias 2 (RoB 2), and certainty of evidence was graded using GRADE. Due to heterogeneity, the data were synthesized qualitatively. The included studies were RCTs of adults with biopsy-confirmed, non-cirrhotic MASH (F2-F3) treated with resmetirom, GLP-1 receptor agonists, or GIP/GLP-1 receptor agonists, while non-randomized studies and pediatric and cirrhotic populations were excluded. This study is limited by the absence of head-to-head trials comparing the three drug classes, as well as by heterogeneity across the included studies, which precluded meta-analysis. The results showed that all active therapies outperformed placebo on at least one biopsy-anchored endpoint. Resmetirom improved both MASH resolution and fibrosis at 52 weeks, with marked low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) reductions but minimal weight change. Semaglutide achieved dose-dependent histologic and metabolic benefits, culminating in dual-endpoint improvement in the phase 3 ESSENCE trial. Liraglutide improved resolution in a small trial, while tirzepatide achieved both endpoints with large, dose-related weight loss. Non-invasive biomarkers paralleled histology, and adverse events were predominantly mild gastrointestinal effects. GRADE assessments indicated low certainty for between-class differences in histologic outcomes, high certainty favoring incretin therapies for weight reduction, and moderate certainty favoring resmetirom for lipid lowering. In conclusion, resmetirom, semaglutide, and tirzepatide each demonstrate clinically meaningful efficacy and tolerability in non-cirrhotic MASH, with distinct metabolic profiles, resmetirom as a lipid-centric, weight-neutral therapy and incretins as weight-centric, pleiotropic agents. Further direct-comparison trials are warranted to clarify their relative benefits on histology and cardiometabolic outcomes.
The National Psoriasis Foundation Primer on GLP-1 Receptor Agonists in Psoriasis: A Review.
JAMA Dermatol
Samip Sheth, Joseph F Merola, Brittany N Weber +12 more
Psoriasis is a chronic immune-mediated disease associated with cardiovascular, metabolic, musculoskeletal, psychiatric, hepatic, kidney, and pulmonary comorbidities. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are approved by the US Food and Drug Administration for type 2 diabetes, obesity, cardiovascular risk reduction, chronic kidney disease, obstructive sleep apnea, and metabolic dysfunction-associated steatohepatitis-conditions common in psoriasis. Emerging evidence suggests GLP-1 RAs and dual glucose-dependent insulinotropic polypeptide/GLP-1 agonists may improve psoriatic skin disease, partly through immune modulation. If confirmed in larger randomized clinical trials, GLP-1-based therapies may offer an opportunity to address both cutaneous disease and cardiometabolic comorbidities. This primer from the US National Psoriasis Foundation Medical Board sought to provide an evidence-informed narrative synthesis and practical considerations to introduce dermatologists to GLP-1 RAs for psoriasis treatment.
Burden and clinical impact of anemia in heart failure: insights from a large observational cohort in Saudi Arabia.
Front Med (Lausanne)
Lama Alfehaid, Omar S Alkhezi, Joud Alfriah +1 more
Anemia is a common comorbidity in heart failure (HF) and is associated with adverse outcomes, yet contemporary real-world data describing its burden and relationship with biomarkers of HF severity remain limited.
[Therapy prospects for post-stroke aphasia].
Zh Nevrol Psikhiatr Im S S Korsakova
A N Bogolepova
Stroke remains a leading cause of disability worldwide. Cognitive impairment is a major consequence, with post-stroke aphasia developing in approximately 30% of patients after a first stroke. Speech impairments substantially reduce quality of life, complicate rehabilitation, and hinder reintegration into daily activities. Patients with aphasia exhibit greater cognitive deficits and an increased risk of vascular dementia, regardless of stroke type. Speech therapy is a primary treatment modality. Neuroplasticity is central to post-stroke recovery, and agents that stimulate neuroplasticity represent a promising therapeutic direction. Cerebrolysin, a pleiotropic drug composed of peptides with neurotrophic properties and free amino acids, can activate neuroplasticity. Recent findings from the Efficacy and Safety of Cerebrolysin in the Treatment of Aphasia After Acute Ischemic Stroke study (ESCAS) demonstrate that combined speech therapy and Cerebrolysin use accelerates recovery of speech functions, suggesting its value as an adjunct in stroke rehabilitation.
Beyond weight loss: tirzepatide as a dual GIP/GLP-1 receptor agonist for obstructive sleep apnea.
Curr Opin Endocrinol Diabetes Obes
Jairo A Noreña, Tugce Akcan, Dimpi Desai
This review summarizes emerging evidence on the use of the dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide in improving obstructive sleep apnea (OSA) outcomes in individuals with obesity.
Evaluation of thyroglobulin autoantibodies in dogs at the time of diagnosis of hypoadrenocorticism and during treatment.
Vet Rec
Christin Emming, Sina Strey, Ina Leiter +4 more
Autoimmune thyroiditis (AIT) may occur more frequently in dogs with hypoadrenocorticism (HA) than previously recognised. The objective of this study was to determine the presence of thyroglobulin autoantibodies (TgAAs) in dogs with HA.
Congenital Adrenal Hyperplasia due to 11β-Hydroxylase Deficiency Presented With Leydig Cell Tumor and Testicular Adrenal Rest Tumors: A Case Report.
Case Rep Endocrinol
Shervin Mossavarali, Faezeh Sehatpour, Shahrzad Mohseni +1 more
Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency is an uncommon disorder characterized by impaired cortisol synthesis, hyperandrogenism, and mineralocorticoid excess. The coexistence of Leydig cell tumors (LCTs) and testicular adrenal rest tumors (TARTs) is rarely reported, highlighting the diagnostic and therapeutic challenges in such cases. A 35-year-old man with a history of hypertension and infertility presented with left testicular masses. His medical history was significant for a prior right orchiectomy, with pathology confirming LCT. Subsequent evaluations revealed azoospermia, elevated adrenal androgen levels, adrenocorticotropic hormone (ACTH) and 17-OH progesterone levels indicative of CAH due to 11β-hydroxylase deficiency. Imaging studies identified left testicular masses and bilateral adrenal myelolipomas. The patient was managed with oral dexamethasone and eplerenone, resulting in normalization of blood pressure and electrolytes. This case highlights the complexity of CAH presentations with overlapping testicular and adrenal pathologies. Patients with such conditions should be closely monitored and regularly checked for common complications to ensure timely intervention and optimal management.
A rare case of dual hormone-secreting pulmonary neuroendocrine tumor causing concurrent Cushing syndrome and acromegaly.
JCEM Case Rep
Dogga Sudhakar, Sourav Debnath, Nishant Jain +2 more
Dual ectopic secretion of adrenocorticotropic hormone (ACTH) and growth hormone-releasing hormone (GHRH) by a single neuroendocrine tumor (NET) is extremely rare. We report a 43-year-old woman presenting with acral enlargement, weight gain, hyperpigmentation, and proximal muscle weakness. Laboratory evaluation revealed elevated cortisol, ACTH, and insulin-like growth factor 1 (IGF-1), consistent with concurrent Cushing syndrome and acromegaly. Imaging demonstrated a left hilar mass, and biopsy confirmed a pulmonary NET with immunohistochemical (IHC) positivity for synaptophysin and chromogranin. Pituitary magnetic resonance imaging (MRI) showed diffuse hyperplasia, suggesting trophic stimulation rather than a primary pituitary adenoma. Surgical resection resulted in normalization of hormone levels, marked clinical improvement, and regression of pituitary enlargement. Although direct histologic confirmation of tumor-derived GHRH was unavailable, the reversible pituitary hyperplasia favors ectopic GHRH-mediated stimulation rather than primary ectopic GH secretion. IHC of the resected tumor demonstrated ACTH positivity, supporting ectopic ACTH secretion. This case highlights the importance of recognizing dual hormone-secreting NETs in patients presenting with overlapping endocrine syndromes, as early detection and complete resection can lead to remission.
Non-arteritic anterior ischaemic optic neuropathy incidence in placebo-controlled clinical trials of liraglutide or semaglutide.
Br J Ophthalmol
Tina Vilsbøll, Dikshit Arun Kumar, Lloyd Paul Aiello +3 more
Risk of non-arteritic anterior ischaemic optic neuropathy (NAION) following exposure to glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes and/or obesity remains unclear. The aim of this study was to investigate NAION incidence across randomised placebo-controlled trials evaluating the GLP-1RAs liraglutide and semaglutide.
Noninvasive Estimation of Left Ventricular End-Diastolic Pressure Through a Mechanical Seal for a Rotary Blood Pump.
Artif Organs
Daisuke Ogawa, Tadashi Motomura, Yasuyuki Shiraishi +5 more
Left ventricular end-diastolic pressure (LVEDP) is an important index of cardiac preload and heart failure (HF) severity. However, direct measurement of LVEDP requires invasive procedures, including local anesthesia and catheter insertion. To address these limitations, we developed a novel LVEDP estimation method based on the relationship between left ventricular pressure and the behavior of the mechanical seal (MS). In this study, we demonstrate that LVEDP can be estimated by measuring pressure inside the MS.
Lasting effects of early-life oxytocin treatment on LTP and episodic memory in a mouse model of Fragile X syndrome.
Neuropsychopharmacology
Jasmine Chavez, Aliza A Le, Julie C Lauterborn +4 more
Deficits in episodic memory are a debilitating feature of Fragile X syndrome (FXS) and other congenital autism spectrum disorders (ASDs). There is evidence that oxytocin (OXT) treatments can improve sociability in persons with ASD and related animal models, encouraging the idea that benefits might extend to cognitive function. We tested this possibility in male FXS model, Fmr1-knockout (KO) mice. Intranasal treatments with OXT or saline were given daily during the second or fifth postnatal week, and effects on social behavior, spatial and episodic memory, and hippocampal synaptic plasticity were assessed in adulthood. Saline-treated Fmr1-KOs exhibited profound deficits in social recognition, object location memory, what-when-where components of episodic memory and long-term potentiation (LTP) in both the CA3-CA1 and lateral perforant path (LPP) systems; NMDAR-mediated components of LPP responses were also impaired. OXT treatments during the second week postnatal normalized all of these functions in Fmr1-KOs assessed in adulthood; this included restoration of initial stages of CA3-CA1 LTP and granule cell NMDAR-mediated currents. In hippocampal slices from naïve adult male Fmr1-KO mice, bath-applied OXT treatment restored LTP in CA1 but not the LPP, indicating pathway-specific effects. Intranasal OXT treatments during the 5th week postnatal did not have enduring effects in either genotype. The present evidence that early OXT treatment corrects a broad range of cognitive and synaptic plasticity deficits in Fmr1-KO mice identifies a clinically plausible strategy for normalizing hippocampal function in ASD and FXS, and highlights the presence of a critical developmental window for effective intervention.
Hemoglobin Nanofibrils as Electrospun Cell Scaffolds to Enhance Primary Satellite Cell Proliferation and Differentiation for Muscle Regeneration.
J Biomed Mater Res A
Qun Chen, Jin Kyo Oh, Vaughan Feisst +3 more
Stem cells are usually sensitive to extracellular matrix (ECM), and an effective synthetic ECM to mimic there in vivo growth surroundings is always desired. Poly(ɛ-caprolactone) (PCL) is a common synthetic material extensively employed for ECMs in medical regeneration applications. However, it lacks inherent bioactivity, which poses limitations to its utility. Our study provides a solution to address this drawback by incorporating hemoglobin nanofibrils (HbFs) into PCL. Leveraging the economical and easily formed HbFs, the resulting electrospun cell scaffolds exhibited improved cell adhesion of muscle satellite cells. Furthermore, these scaffolds facilitated enhanced cell proliferation, cell infiltration into the scaffold, and higher levels of expression of differentiation-related proteins. This study demonstrates the feasibility of HbFs-incorporated electrospun scaffolds as a promising ECM substitute for muscle stem cell-based regeneration therapies.
Semaglutide 2.4 mg Cardiometabolic Long-Term Effects in Patients With Obesity or Overweight in a Real-World Setting: A Retrospective Cohort Study in the United States (SMILE).
Diabetes Obes Metab
Aleksandrina Ruseva, Wojciech Michalak, Matthew Bassan +9 more
To evaluate the real-world associations between semaglutide 2.4 mg and cardiometabolic comorbidities, biomarkers and cardiovascular risk among adults with overweight or obesity.
Blamed but not at fault: Anti-obesity medication adverse effects misidentified as perioperative complications - a comprehensive review and medicolegal warning for anesthesiologists.
Korean J Anesthesiol
Hyun Jeong Kwak, Jung Ju Choi, Dongchul Lee +1 more
The rapid proliferation of anti-obesity medications (AOMs), including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agonist tirzepatide, and non-incretin agents, including orlistat, phentermine, and bupropion/naltrexone, has created an underappreciated perioperative patient safety hazard. Existing guidelines have focused narrowly on GLP-1 RAs and aspiration risk, leaving some critical gaps unaddressed: (1) the misidentification trap, whereby drug-induced adverse effects, including acute pancreatitis, bowel obstruction, sudden visual loss, and neuropsychiatric dysfunction, are clinically and radiographically indistinguishable from surgical or anesthetic complications, exposing clinicians to unwarranted blame, and (2) the full perioperative risk profile of non-GLP-1 AOM classes. This narrative review synthesizes the current pharmacovigilance evidence, consensus guidelines, and clinical case data to address these gaps. Non-arteritic anterior ischemic optic neuropathy (NAION) from semaglutide (HR 7.64; World Health Organization safety alert 2025) may be attributed to anesthetic corneal injury, emotional lability may be misinterpreted as emergence delirium, drug-induced pancreatitis from GLP-1 RAs (adjusted HR 9.09 vs. comparator) may be misattributed to the operating surgeon, and bowel obstruction from premature postoperative GLP-1 RA resumption has prompted unnecessary re-laparotomy. Structured preoperative AOM documentation, explicit postoperative hold orders, and the inclusion of drug etiology in postoperative differentials constitute the defensible standard of care in the era of pharmacological obesity management.
Nanotherapeutic Strategies for Osteoarthritis: Targeting Aging, Metabolism and Inflammation.
Int J Nanomedicine
Zhenglin He, Yimeng Chen, Kai Zhao +6 more
Osteoarthritis (OA) is no longer viewed as a mere "wear-and-tear" disease, but rather as a multifactorial joint failure syndrome driven by cellular senescence, metabolic dysregulation, and low-grade chronic inflammation. These pathological pillars synergistically disrupt cartilage homeostasis, subchondral bone remodeling, and synovial inflammation, collectively fueling disease progression. While conventional therapies offer only symptomatic relief, they fail to reverse or reprogram the underlying pathological microenvironment. Consequently, there is an urgent need to develop disease-modifying interventions that can simultaneously target these pathological pillars. Here, we critically examine how nanomaterial-based platforms-leveraging tailorable surface chemistry, cartilage-penetrating dimensions, and stimuli-responsive cargo release-enable precision targeting of these interconnected mechanisms. We highlight advances in senolytic delivery for senescent cell clearance, redox-modulating nanozymes for metabolic reprogramming, and immunoregulatory strategies for macrophage repolarization, emphasizing designs that transcend passive drug delivery to actively remodel the joint microenvironment. By integrating mechanistic insights with engineering innovation, this review outlines a roadmap for next-generation disease-modifying nanomedicines that promise not merely to slow OA progression, but to restore the biological clock of the joint. We also discuss current translational barriers and propose future directions for personalized OA therapy.