Trojan horse-inspired spatiotemporal strategy augments cartilage regeneration by enhancing mitochondrial energy production.

Treating osteoarthritis (OA) presents a significant challenge due to the fact that conventional intra-articular injections only achieve superficial penetration and uncontrolled drug release. Here, the amino-modified cationic mesoporous silica nanoparticles were covalently conjugated with cartilage-targeted peptides to form a Trojan horse-like architecture for enveloping the prochondrogenic fucoidan. The hydrogel microsphere, consisting of photocurable GelMA and ChSMA, were fabricated using a microfluidic platform for cargo delivery. The cationic targeting nanoparticle-hydrogel microsphere@fucoidan (CTNM@FU) possess three-step programmable characteristics that enable responsive transport toward injured cartilage, effective penetration of the cartilage matrix and selective entry into chondrocytes, escape from lysosomes, and release of bio-activators. The impaired cartilage metabolism was significantly reversed upon co-culturing with CTNM@FU. Intra-articular administration of CTNM@FU not only mitigated cartilage degeneration but also expedited de novo cartilage formation. Mechanistically, CTNM@FU protected cartilage by activating SIRT3, enhancing mitochondrial energy and countering aging. Collectively, a spatiotemporally guided strategy enables more precise treatments for degenerative joint disorders.