Synergistic targeting of senolytic and senomorphic action with dual-engineered biomimetic macrophage nanovesicles for mitigating osteoarthritis.

Abstract

Osteoarthritis (OA), a leading cause of chronic disability worldwide, is increasingly recognized to be driven by the accumulation of senescent chondrocytes (sCDs) and their deleterious pro-inflammatory senescence-associated secretory phenotype (SASP). Existing therapies, including senolytics and senomorphics, lack cell-specific targeting and fail to neutralize the heterogeneous components of SASP. Here, we develop a dual-engineered macrophage membrane camouflaged, self-assembled nanoplatform (BS@MD) that combines senolytic and senomorphic functions synergistically. Within the OA microenvironment, BS@MD acts as a "nanosponge" to broadly neutralize SASP through overexpressed cytokine receptors derived from LPS-primed macrophage membranes. This process alleviates chondrocyte senescence and facilitates the phenotypic shift of pro-inflammatory M1 macrophages toward an anti-inflammatory M2 state. Additionally, surface conjugation with an anti-DPP4 antibody enables BS@MD to selectively target sCDs and disassemble in the acidic lysosomal environment, releasing bortezomib (BTZ) and sabutoclax (Sab). These agents act synergistically to inhibit the NF-κB and BCL-2 pathways, thereby inducing sCDs apoptosis and suppressing SASP production, effectively disrupting the senescence-inflammation feedback loop. In the anterior cruciate ligament transection (ACLT)-induced OA mouse model and naturally aged OA mouse model, BS@MD enhances joint retention, reduces cartilage degradation and inflammation, and promotes cartilage homeostasis. Overall, this work pioneers a dual-pronged senotherapeutic strategy for non-surgical OA management.