Neutrophil Membrane-Camouflaged siRNA Nanoplatform Targeting IL-33 Attenuates Osteoarthritis Through Autophagy-Dependent Senescence Regulation

Osteoarthritis (OA) imposes a substantial health and economic burden globally. Currently, there is a lack of disease-modifying osteoarthritis drugs (DMOADs). This study aimed to elucidate the relationship between chondrocyte senescence and OA progression, as well as to develop an effective siRNA nanodelivery platform for OA treatment. We engineered neutrophil membrane-coated, siIL33-loaded nanoparticles (NM-NP-siIL33) for OA management. The therapeutic efficacy of NM-NP-siIL33 was evaluated through both in vitro and in vivo experiments. Our findings revealed that IL-33 expression was significantly upregulated in damaged articular cartilage in both young and aged mice following anterior cruciate ligament transection (ACLT) surgery. In vitro experiments demonstrated that IL-33 promotes chondrocyte senescence by inhibiting cellular autophagy via activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Additional in vivo studies showed that NM-NP-siIL33 effectively delivered siIL33 to target cells within OA tissues, thereby mitigating the degradation of articular cartilage. Our results suggest that IL-33 plays a critical role in OA progression by accelerating chondrocyte senescence. Furthermore, NM-NP-siIL33 represents a promising therapeutic strategy for managing OA.