Efferocytosis, an intrinsic regulatory mechanism to eliminate apoptotic cells, will be suppressed due to the delayed apoptosis process in aging-related diseases, such as osteoarthritis (OA). In this study, cartilage lesion-localized hydrogel microspheres are developed to remodel the in situ efferocytosis to reverse cartilage senescence and recruit endogenous stem cells to accelerate cartilage repair. Specifically, aldehyde- and methacrylic anhydride (MA)-modified hyaluronic acid hydrogel microspheres (AHM), loaded with pro-apoptotic liposomes (liposomes encapsulating ABT263, A-Lipo) and PDGF-BB, namely A-Lipo/PAHM, are prepared by microfluidic and photo-cross-linking techniques. By a degraded porcine cartilage explant OA model, the in situ cartilage lesion location experiment illustrated that aldehyde-functionalized microspheres promote affinity for degraded cartilage. In vitro data showed that A-Lipo induced apoptosis of senescent chondrocytes (Sn-chondrocytes), which can then be phagocytosed by the efferocytosis of macrophages, and remodeling efferocytosis facilitated the protection of normal chondrocytes and maintained the chondrogenic differentiation capacity of MSCs. In vivo experiments confirmed that hydrogel microspheres localized to cartilage lesion reversed cartilage senescence and promoted cartilage repair in OA. It is believed this in situ efferocytosis remodeling strategy can be of great significance for tissue regeneration in aging-related diseases. This work introduced the innovative A-Lipo/PAHM microsphere, localizing to degraded cartilage. The released A-Lipo is internalized by the Sn-chondrocytes, subsequently, the apoptotic Sn-chondrocytes are eliminated via efferocytosis. Furthermore, recruited stem cells played a role in promoting the regeneration of degraded cartilage. This strategy serves as a promising approach for reversing cartilage senescence. image
基金:
National Natural Science Foundation of China; Talent Development Plan for High-level Public Health Technical Personnel Project [-02-23]; Beijing Natural Science Foundation Haidian Original Innovation Joint Fund [L212010]; Beijing Tongren Hospital Top Talent Project [2024-YJJ-BJL-016]; Shanghai Municipal Health and Family Planning Commission [2022XD055, 202140128]; Summit talent of Beijing Hospital Administration Center; [52273133]; [82272473]; [22105127]