RADA16 and SAAP148 Peptide‐Modified Collagen Self‐Assembled Hydrogels for Accelerated Healing of Infected Wounds

Abstract Infected wounds suffer from limited self‐healing, persistent bacterial infections, prolonged inflammation, and oxidative wound microenvironment. While anti‐bacterial peptides such as SAAP148 demonstrate remarkable efficacy against drug‐resistant pathogens, their clinical application is hindered by rapid inactivation and uncontrolled burst release. To address these limitations, collagen type I (Col I) is integrated with self‐assembling peptide RADA16 to develop a novel self‐assembled nano‐micro structured hydrogel (Col I‐RADA16, CR) without chemical cross‐linkers. This unique design leverages the micron‐scale porous structure of Col I and the nanofibrous architecture of RADA16, resulting in a hydrogel with excellent mechanical properties, sustained SAAP148 release, and enhanced bioactivity. CR not only promotes fibroblast adhesion, migration, and proliferation, but when loaded with SAAP148 (Col I‐RADA16‐SAAP148, CRS), effectively inhibits bacterial infection, enhances macrophage polarization and accelerates wound healing in vivo. Importantly, histological and immunohistochemical analyses revealed that the CRS hydrogel significantly enhances regeneration of skin appendages (e.g., hair follicles and glands) by action of CK5 and CK14 in the ERBB/MAPK, mTOR/PI3K‐Akt, JNK/p38 MAPK signaling axes, significantly surpassing the performance of traditional collagen or gelatin sponges. This innovative dual‐scale design and cross‐linker‐free fabrication strategy offers a versatile and clinically translatable platform for infected wound healing, addressing critical limitations in current wound care technologies.