Mechanically adaptive dual-crosslinked hydrogel integrated with metal-phenolic cell backpacks for active keloid therapy.

Abstract

Keloids are invasive, highly recurrent fibroproliferative disorders. Clinical samples reveal a pathological pattern characterized by dysregulated extracellular matrix (ECM) remodeling, reduced NK-cell infiltration, and elevated TGF-β1. Current monotherapies have limited efficacy, and local delivery systems fail to achieve deep penetration and sustained effects due to the dense ECM barrier. To address these, we propose an active strategy of mechanically adaptive carrier delivering functionalized immune cells and develop a pH-responsive dual-crosslinked hydrogel (OR-Mg@NK@Gel) with oxyresveratrol‑magnesium (OR-Mg) metal-phenolic cell backpacks. The hydrogel is fabricated from methacrylated oxidized hyaluronic acid and 8-arm polyethylene glycol amine via sequential crosslinking of dynamic Schiff base and blue light-induced covalent networks, tuning the storage modulus to ~400 Pa to provide a soft, cell-compatible matrix with appropriate injectability and structural stability. It has interconnected macropores and pH-responsive degradation, supporting cells and enabling spatiotemporally controlled co-release of cells and therapeutics, overcoming compliance mismatch and drug burst release of conventional hydrogels. OR-Mg@NK cell backpacks are constructed by electrostatically associating surface-charge-reversed OR-Mg nanoparticles predominantly with NK cell membranes. This non-covalent modification preserves cell viability while enhancing NK cell chemotaxis via PI3K/AKT activation, enabling active penetration through dense collagen barriers. By combining hydrogel-mediated local retention with NK-cell-mediated active migration, OR-Mg@NK@Gel enables enhanced penetration through the dense ECM barrier and broader intralesional distribution. In a nude mouse keloid model, it achieved 90.62% volume inhibition and 94.26% weight inhibition, both significantly outperforming 5-fluorouracil. It also improved disordered collagen arrangement and remodeled immune microenvironment toward an anti-fibrotic state. This work provides a novel paradigm for designing efficient cell delivery systems targeting dense fibrotic tissues and holds promising translational potential.