Injectable microgels carrying engineered biomimetic nanoparticles for osteoarthritis therapy via dual-targeted senescent chondrocyte clearance and endogenous repair promotion

The accumulation of senescent chondrocytes contributes significantly to osteoarthritis (OA) progression, establishing a self-perpetuating cycle of cartilage deterioration. Current therapeutic strategies remain limited by inadequate precision to target senescent populations and the inability to simultaneously trigger endogenous regenerative processes. Herein, we developed a hydrogel microsphere system to locally eliminate senescent chondrocytes, thereby creating a permissive microenvironment and facilitating endogenous stem cell recruitment to accelerate cartilage repair. Specifically, chondrocyte membranes (CM) overexpressing natural killer group 2 member D (NKG2D) receptors (NCM) were fabricated via plasmid transfection and extrusion to target upregulated NKG2D ligands on senescent cells. The fusion of ABT263-loaded liposomes (A-lipo) with NCM produced the senolytic ANCM nanoparticles. Subsequently, ANCM and SDF-1α were co-encapsulated into methacrylic anhydride (MA)-modified hyaluronic acid (HA) hydrogel microspheres (SHM) using microfluidics. The resulting ANCM@SHM exhibited remarkable biocompatibility and a dual-phase functionality: hydrogel-enhanced articular retention followed by ANCM-mediated active targeting of senescent chondrocytes. Functional assessments validated the effective clearance of senescent chondrocytes, achieved by inducing mitochondrial outer membrane permeabilization (MOMP), was accompanied by metabolic reprogramming of surviving chondrocytes toward an anabolic phenotype. Simultaneously, sustained SDF-1α release induced robust mesenchymal stromal cells (MSCs) homing and chondrogenic differentiation, resulting in synergistic cartilage remodeling. <i>In vivo</i> evaluations demonstrated a pronounced attenuation of OA progression, attributable to synergistic remodeling of the joint microenvironment. This multidimensional engineering strategy disrupts the vicious cycle of senescence-associated cartilage degeneration by integrating targeted senolysis with stem cell-mediated regeneration, providing a promising therapeutic approach for OA management.