Acellular matrix microgel assembly integrated with curcumin-loaded ZIF-8 nanoparticles and simvastatin promotes microfracture-based articular cartilage repair via pyroptosis inhibition, endogenous BMSC recruitment, and hyaline chondrogenic differentiation.

Abstract

Articular cartilage repair remains a major clinical challenge. Although microfracture is widely employed, it often leads to fibrocartilage formation rather than functional hyaline cartilage regeneration. Herein, we develop an injectable cartilage acellular matrix (CACM) microgel assembly integrating curcumin-loaded ZIF-8 nanoparticles (Cur@ZIF-8) and simvastatin (SIM) to improve microfracture-based cartilage repair. The dynamically crosslinked microgel assembly exhibits good injectability, tissue adhesion, shape adaptability, and an interconnected microporous structure, thereby facilitating material retention, nutrient exchange, BMSC anchorage and infiltration at the defect site. Sustained SIM release promotes endogenous BMSC recruitment from the bone marrow cavity, while Cur@ZIF-8 enables pH-responsive Cur release in the inflammatory microenvironment and inhibits BMSC pyroptosis through the NLRP3/Caspase-1/GSDMD pathway. In addition, the CACM matrix provides cartilage-specific biochemical cues, including Col II and GAGs, to promote hyaline chondrogenic differentiation. In a rabbit cartilage defect model combined with microfracture surgery, the (Cur@ZIF-8)/SIM@CACM microgel assembly significantly enhances defect filling, extracellular matrix deposition, Col II expression, and hyaline cartilage-like tissue regeneration. This multifunctional injectable microgel assembly offers a promising strategy for improving microfracture-based articular cartilage repair by integrating endogenous cell recruitment, pyroptosis inhibition, and hyaline chondrogenic induction.