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.