This study presents a novel approach to reverse cartilage senescence in osteoarthritis (OA) by remodeling efferocytosis using lesion-localized hydrogel microspheres. The researchers developed aldehyde- and methacrylic anhydride (MA)-modified hyaluronic acid hydrogel microspheres (AHM), loaded with pro-apoptotic liposomes (containing ABT263) and PDGF-BB, termed A-Lipo/PAHM. These microspheres were designed to target degraded cartilage in OA, promoting the apoptosis of senescent chondrocytes (Sn-chondrocytes) and facilitating their removal via efferocytosis by macrophages. This process helps restore the function of normal chondrocytes and maintains the chondrogenic differentiation capacity of mesenchymal stem cells (MSCs). In vitro experiments showed that A-Lipo induced apoptosis of Sn-chondrocytes, which were then phagocytosed by macrophages, leading to the activation of efferocytosis and the removal of "zombie" cells. This process reduced the secretion of senescence-associated secretory phenotype (SASP) factors, which are harmful to tissue regeneration. In vivo experiments confirmed that the microspheres localized to cartilage lesions in an OA model, reversed cartilage senescence, and promoted cartilage repair. The microspheres also recruited endogenous stem cells to the damaged area, enhancing tissue regeneration. The study highlights the importance of efferocytosis in clearing senescent cells and restoring tissue homeostasis in aging-related diseases. The lesion-localized hydrogel microspheres provide a promising strategy for tissue regeneration by targeting the specific areas of cartilage damage and promoting the clearance of senescent cells. This approach could be applicable to other aging-related diseases, offering a new therapeutic avenue for tissue repair and regeneration. The results demonstrate that the in situ remodeling of efferocytosis through lesion-localized microspheres is a significant advancement in the treatment of OA and other degenerative diseases.This study presents a novel approach to reverse cartilage senescence in osteoarthritis (OA) by remodeling efferocytosis using lesion-localized hydrogel microspheres. The researchers developed aldehyde- and methacrylic anhydride (MA)-modified hyaluronic acid hydrogel microspheres (AHM), loaded with pro-apoptotic liposomes (containing ABT263) and PDGF-BB, termed A-Lipo/PAHM. These microspheres were designed to target degraded cartilage in OA, promoting the apoptosis of senescent chondrocytes (Sn-chondrocytes) and facilitating their removal via efferocytosis by macrophages. This process helps restore the function of normal chondrocytes and maintains the chondrogenic differentiation capacity of mesenchymal stem cells (MSCs). In vitro experiments showed that A-Lipo induced apoptosis of Sn-chondrocytes, which were then phagocytosed by macrophages, leading to the activation of efferocytosis and the removal of "zombie" cells. This process reduced the secretion of senescence-associated secretory phenotype (SASP) factors, which are harmful to tissue regeneration. In vivo experiments confirmed that the microspheres localized to cartilage lesions in an OA model, reversed cartilage senescence, and promoted cartilage repair. The microspheres also recruited endogenous stem cells to the damaged area, enhancing tissue regeneration. The study highlights the importance of efferocytosis in clearing senescent cells and restoring tissue homeostasis in aging-related diseases. The lesion-localized hydrogel microspheres provide a promising strategy for tissue regeneration by targeting the specific areas of cartilage damage and promoting the clearance of senescent cells. This approach could be applicable to other aging-related diseases, offering a new therapeutic avenue for tissue repair and regeneration. The results demonstrate that the in situ remodeling of efferocytosis through lesion-localized microspheres is a significant advancement in the treatment of OA and other degenerative diseases.