Injection-free piperine-loaded hyaluronic acid-modified proposomes rejuvenate cartilage deterioration in MIA-osteoarthritic rats.

Osteoarthritis (OA) is a degenerative disorder impacting individuals' quality of life. The current medications fail to halt the disease's progression or attain long-term safety and efficacy. Piperine (PIP) is a natural chondroprotective agent, acting via its anti-inflammatory and antioxidant effects. However, it suffers from poor solubility that limits its pharmacological activity. Herein, a novel PIP-loaded hyaluronic acid-modified proposomes (PIP-HAPs) was investigated for the first time by integrating the penetration-enhancing effects of both proposomes nanovesicles and hyaluronic acid as a non-invasive transdermal treatment for OA. The optimized PIP-HAPs showed a particle size 108 ± 3.71 nm, zeta potential -31.9 ± 0.62 mV, and an entrapment efficiency 92.3% ± 0.64, with a sustained drug release over 48 h. The ex vivo permeability test exhibited a remarkable enhancement in PIP-HAPs' transdermal permeability relative to the conventional gel. Also, confocal laser microscopy photographs revealed the deepest penetration into the articular cartilage in the PIP-HAPs treated group. A comprehensive preclinical study using a mono-iodoacetate (MIA)-induced osteoarthritis rat model demonstrated that PIP-HAPs exhibited the most significant anti-arthritic efficacy, mitigating OA progression. Conclusively, PIP-HAPs are a novel, nanodermatological approach that demonstrates a significant antinociceptive effect, preserves the articular cartilage structure, and restores joint mobility, thereby offering a promising non-invasive treatment for OA.