A self-assembled nano micelle-exosome with high selectivity and penetrability achieves precise intracartilage lipid delivery

To address the challenge of extremely low drug bioavailability in osteoarthritis (OA) cartilage, we developed a self-assembled micelle-exosome system (Mic-Exo) tailored to the specific characteristics of OA cartilage. The hydrophobic lipid layer of Mic-Exo enables efficient loading of therapeutic lipids (DHA), while the incorporation of 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP) reverses surface charge to enhance penetration. The hydrophilic polyethylene glycol (PEG) shell protects Mic-Exo from rapid clearance and undesired endocytosis. The amphiphilic monomers in the micelle incorporate a matrix metalloproteinase (MMP)–responsive peptide (GPLGVRG), which undergoes hydrolysis in response to elevated MMP activity at lesion sites, enabling rapid uptake by nearby chondrocytes. In vitro experiments confirmed the high selectivity of Mic-Exo for OA chondrocytes and its rapid penetration capabilities. In animal models, the DHA/Mic-Exo group significantly retarded OA progression, as evidenced by reduced Osteoarthritis Research Society International (OARSI) scores and mitigated cartilage thickness loss.