<p>Osteoarthritis (OA), a prevalent chronic degenerative joint disorder, affects hundreds of millions of people worldwide and has become a leading cause of joint pain and functional impairment in middle-aged and elderly populations. It not only severely compromises patients’ quality of life but also imposes a significant socioeconomic burden on public health systems. Targeting key pathological processes in OA, such as inflammatory responses, chondrocyte apoptosis, and dysregulated autophagy, an injectable liposomal system named RAPA@Lipo/rhCol Ⅲ were developed in this study. This system consisted of rapamycin-loaded liposomes surface-modified with recombinant human collagen type Ⅲ (rhCol Ⅲ). It enabled sustained release of rapamycin to precisely inhibit the mTOR pathway, thereby exerting synergistic biological effects including anti-inflammation, inhibition of chondrocyte apoptosis, and promotion of autophagy. Moreover, the surface collagen modification enhanced the system’s biocompatibility and provided essential matrix microenvironment cues and bioactive signals for cartilage repair. Experimental results demonstrated that RAPA@Lipo/rhCol Ⅲ effectively scavenged reactive oxygen species in chondrocytes, promoted cell proliferation and cartilage matrix synthesis, and modulated the expression of autophagy- and inflammation-related genes, thereby synergistically achieving structural and functional restoration of OA cartilage across multiple dimensions. The integrated “disease modulation-tissue repair” strategy proposed in this study offerd a novel approach and experimental evidence for targeted therapy and functional regeneration in osteoarthritis.</p> Graphical Abstract <p></p>