An Aggrecanase-Responsive Delivery Hydrogel System of miRNA-17 Facilitates Microfracture-Mediated Articular Cartilage Regeneration by Reprogramming Hostile Inflammatory Niche

In situ articular cartilage (AC) regeneration is a meticulously coordinated process. Microfracture has been the most extensive clinical approach in AC repair, but it faces challenges such as matrix degradation, generation, and remodeling within a local inflammatory microenvironment. So far, it remains a challenge to establish a multistage regulatory framework for coordinating these cellular events, particularly the immune response and chondrocyte proliferation in microfracture-mediated AC repair microenvironments, which is crucial for promoting AC regeneration quality. At present, the excessive inflammatory response after microfracture can chronically activate the nuclear factor-κB (NF-κB) pathway, increasing production of matrix-degrading enzymes like matrix metalloproteinases (MMPs) and aggrecanases, which in turn accelerate cartilage matrix degradation and worsen the injury. Herein, we develop a novel enzyme-responsive, self-assembling hydrogel composed of silk fibroin and an Aggrecanase-2 (ADAMTS5)-sensitive peptide. This hydrogel targets ADAMTS5, a key enzyme overexpressed in the postinjury inflammatory microenvironment, enabling dynamic drug release based on inflammation levels. We then incorporated miRNA-17-3p (miR-17-3p) into lipid nanoparticles and loaded this miRNA delivery system into the hydrogel to inhibit NF-κB signaling upstream of ADAMTS5. This strategy created a targeted positive regulatory feedback mechanism, fundamentally solving the problem of modulating the ADAMTS5-related inflammasome pathway while boosting chondrocyte expansion in the early stage. In vivo studies in microfracture-mediated cartilage repair models demonstrated that the ADAMTS5-responsive hydrogel with miR-17-3p achieves superior repair outcomes. This research offers a logic-based and multistaged strategy for chronologically regulating the inflammatory microenvironment, which has research value and practical application prospects in the treatment of AC injuries.