Breathable palladium hydride hydrogels mediated “head and tail” co-blocking HMGB1-RAGE axis strategy for diabetic foot ulcer treatment

Abstract

Diabetes patients suffer from severe chronic consequences known as diabetic foot ulcers (DFUs), for which there are no particular therapy options. The inflammatory and oxidative microenvironments in DFUs stimulate the secretion of high mobility group box-1 (HMGB1), which binds with the receptor of advanced glycation endproducts (RAGE), causing inflammatory cascade reactions and immune microenvironment (IME) disorder, further exacerbating DFUs damage. Strategies targeting the HMGB1-RAGE axis to end this vicious loop are still lacking. This study proposes a novel strategy based on “breathable hydrogels” to achieve HMGB1-RAGE axis “head and tail” co-blocking to regulate the IME for DFUs treatments. Specifically, with palladium hydride (PdH) nanocubes as the functional structure, a hydrogel dressing was prepared from a double cross-linking network of biocompatible alginate and polyacrylamide and modified with trehalose as the network-repairing agent. Mechanistically, the obtained hydrogels can “inhale” the excess accumulated reactive oxygen species, inhibiting HMGB1 secretion, the “head” of the HMGB1-RAGE axis. Meanwhile, H₂ “exhaled” from the hydrogels can suppress the expression of intracellular RAGE, thus blocking the HMGB1-RAGE axis and breaking the vicious cycle. The proposed “head and tail” co-blocking strategy based on “breathable hydrogels” offers a highly efficient, safe, and facile therapeutic protocol for DFUs.