An intelligent nano-engineered PLGA@IGF-1 hydrogel for programmed immune modulation and tendon regeneration via IGF-1R/AKT signaling

Tendon repair remains a major clinical challenge, largely because current strategies often fail to simultaneously achieve early inflammatory control and subsequent matrix remodeling. To address this problem, we developed a dynamically responsive nano-hydrogel, CAPP@IGF-1, composed of 3-carboxyphenylboronic acid-modified chitosan, polyvinyl alcohol, and IGF-1-loaded PLGA microspheres, which were integrated through phenylborate ester crosslinking. The hydrogel exhibited favorable self-healing behavior together with enhanced mechanical properties, with an elastic modulus of 4.5 MPa and a toughness of 15.3 MJ/m³, enabling it to maintain local structural stability under the complex dynamic conditions of tendon repair. Under the acidic inflammatory microenvironment, CAPP@IGF-1 enabled controlled local release of IGF-1 and activated the IGF-1R/AKT signaling pathway, thereby markedly promoting macrophage reprogramming from the pro-inflammatory M1 state to the pro-reparative M2 state. This was accompanied by suppression of IL-6, IL-2, and TNF-α and upregulation of IL-10, leading to the establishment of a local immune microenvironment favorable for repair. On this basis, the hydrogel further promoted tendon stem/progenitor cell migration, proliferation, extracellular matrix remodeling, and more ordered collagen deposition. In a rabbit tendon injury model, CAPP@IGF-1 notably reduced peritendinous adhesion, and enhanced the mechanical recovery of repaired tendons. Collectively, CAPP@IGF-1 achieves stage-specific intervention during tendon healing through the combined effects of a dynamically crosslinked network, enhanced mechanical properties, and intelligent IGF-1 release. This study demonstrates the feasibility of using materials design to connect inflammatory microenvironment regulation with tissue regeneration and provides a new strategic basis for the precise repair of complex tendon injuries.