Fig. 7

Schematic representation of dual therapeutic approaches for lysosomal dysfunction in OA, with a focus on the restoration of lysosomal acidity and the repair of lysosomal membranes. The restoration of lysosomal acidity is facilitated by the delivery of acidic nanoparticles designed to release their contents within the acidic lysosomal environment, thereby enhancing the degradation of hydroxyapatite crystallites. Concurrently, the delivery of functional molecules such as Hsp70 alleviates LMP and promotes lysosomal membrane repair. The repair mechanisms involve three distinct pathways: a ANXA7-mediated repair, where ANXA7 is recruited to the lysosomal membrane upon calcium influx. b ESCRT-mediated repair, involving the activation of ESCRT-III components and Ca²⁺-binding protein ALIX or ESCRT-I/II pathways in response to endolysosomal membrane damage, leading to the formation of a higher-order structure that closes the membrane breach by ATPase VPS4. c ASM-mediated repair, where ASM activity induces caveolae formation, followed by membrane closure and internalization of merged caveolae, thus restoring lysosomal membrane integrity. These strategies are crucial for mitigating lysosome-induced chondrocyte apoptosis and are highlighted as necessary for lysosome-targeting strategies in OA therapy. MV matrix vesicle, ASM acid sphingomyelinase, Hsp70 heat shock protein 70, LMP lysosomal membrane permeabilization, LAMPs lysosome-associated membrane proteins