Transdermally administered nanozymes-infused F127/methylcellulose hydrogel for osteoarthritis relief via immunomodulatory pathways

Osteoarthritis (OA) is a debilitating condition characterized by chronic inflammation, oxidative stress, hypoxia, angiogenesis-driven pain, and cartilage degradation, thus presenting significant therapeutic challenges. Herein, we introduce a wearable percutaneous hydrogel (Pluronic F127/methylcellulose) encapsulation platform, designed to address the multifaceted pathology of OA through a synergistic integration of multifunctional components. This nanomedicine-hydrogel system incorporates platelet-derived extracellular vesicles (pEVs) for inflammation delivery, phototherapeutic molybdenum disulfide (MoS2), capsaicin (CAP) and diferuloylmethane (DIF) for potent anti-inflammatory and antioxidative effects and hydrogen-bonded organic frameworks (HOFs) to enhance drug encapsulation and conductivity. Experimental findings demonstrated the pEV/MoS2/DIF/CAP NZHOF@F127/MC's ability to mitigate inflammation by promoting macrophage polarization from the M1 to the M2 phenotype, alleviate oxidative stress, inhibit angiogenesis, and modulate hypoxic microenvironments through the percutaneous phototherapeutic pEV/MoS2/DIF/CAP NZ-HOF@F127/MC. In vivo studies in a rat model of OA revealed substantial reductions in joint inflammation, enhanced cartilage regeneration, and improved mobility following near-infrared (NIR)-triggered phototherapy. The pEV/MoS2/DIF/CAP NZ-HOF@F127/MC's multifaceted mechanisms, including precise drug delivery, controlled release, and on-demand photo-responsiveness, underscore its transformative potential for OA management. These findings present a promising therapeutic strategy for OA, addressing inflammation, oxidative stress, and joint lesion mitigation, with strong potential for clinical translation.