HOF-Stabilized Apple EV Nanocargo in an NIR-Responsive Hydrogel Enables On-Demand Therapeutic Modulation for Transdermal Deep-Joint Osteoarthritis Therapy.

Osteoarthritis (OA) is driven by intertwined pathological processes, including chronic inflammation, oxidative stress, immune imbalance, hypoxia, and aberrant angiogenesis, while current noninvasive therapies remain limited by insufficient deep-joint delivery and poor multidimensional regulation. Here, an extracellular vesicle (EV)-centered, near-infrared (NIR)-responsive transdermal platform is developed to address these challenges. Apple-derived extracellular vesicles (AEVs) are used as intrinsically bioactive nanocarriers to co-deliver berberine (BBR) and piperine (PIP), and are integrated into a biocompatible dextran/alginate hydrogel containing graphene oxide (GO). Under NIR stimulation, GO provides on-demand energy conversion that supports mild hyperthermia-assisted barrier loosening together with potential photo-redox-associated microenvironment modulation, thereby enhancing local therapeutic availability while maintaining a safe thermal window. In vivo assessment of TRPV1 expression and tight-junction-related responses provides supportive indication for transport-associated modulation, whereas ex vivo diffusion findings are interpreted as barrier-level permeation evidence rather than direct confirmation of in vivo mechanisms. In an OA rat model, the NIR-activated platform is associated with reduced joint inflammation and edema, attenuated oxidative stress, improved macrophage polarization toward an anti-inflammatory phenotype, enhanced gait-related joint function, and preservation of cartilage structure. This study establishes a noninvasive, stimulus-responsive transdermal strategy for localized and multifaceted OA microenvironment modulation.