A sulfated chitosan-driven immune-ECM reprogramming strategy to break the vicious cycle of aged wound healing.

Abstract

Chronic wounds in the elderly are characterized by persistent inflammation and excessive extracellular matrix (ECM) degradation, which form a self-perpetuating vicious cycle that impedes healing and increases morbidity. Here, we identify sulfated chitosan (SCS) as an a synthetic glycosaminoglycan capable of disrupting this pathological "ECM degradation-immune imbalance" cycle and promoting robust skin wound repair in aged mice. SCS activates JAK2-STAT3/STAT6 signaling to rebalance M1/M2 macrophage polarization, while simultaneously enhancing phosphoadenosine phosphosulfate (PAPS) production and sulfonate-group trafficking. These coordinated actions collectively improved collagen deposition, angiogenesis, and glycosaminoglycan (GAG) content within the wound microenvironment. Using Sulf2 knockdown and overexpression models, we further show that chitosan-anchored sulfonate groups are required for driving macrophages toward an M2 phenotype, whereas free sulfonate groups facilitate glycosaminoglycan biosynthesis. These coordinated immune and matrix effects lead to enhanced collagen organization, angiogenesis, and glycosaminoglycan deposition within the aged wound microenvironment.Together, this work establishes SCS as a materials-driven immune-ECM reprogramming strategy and highlights its translational potential for the treatment of age-associated chronic wounds.