# pH-responsive and dual-dynamically crosslinked metal-phenolic hydrogel for synergistic macrophage and Th17/Treg reprogramming in diabetic wounds

## TL;DR

A new hydrogel system helps heal diabetic wounds by regulating both innate and adaptive immune responses through pH-responsive properties.

## Contribution

The CSp-OxD@Cu2+/G hydrogel system is novel for its dual-dynamic crosslinking and immune-modulating effects on macrophages and Th17/Treg cells.

## Key findings

- The hydrogel provides a self-healing and adhesive barrier for diabetic wounds.
- Cu2+/G nanoparticles are released in response to local pH, reprogramming immune cells.
- The system regulates both innate and adaptive immunity to promote wound healing.

## Abstract

In recent years, there has been a progressive increase in the cumulative number of individuals afflicted with diabetic wounds, elevating this condition to a global public health concern of significant magnitude. The disruption of the immune microenvironment is recognized as a critical factor impeding the healing process of diabetic wounds. Nevertheless, existing research has predominantly concentrated on innate immune regulation, particularly targeting macrophages, while often overlooking adaptive immunity, which plays an equally vital role within the immune microenvironment. To address both innate and adaptive immune remodeling in diabetic wounds, the CSp-OxD@Cu2+/G hydrogel system has been developed. This system features a dual-dynamically crosslinked structure formed through Schiff base and borate ester bonds, with Cu2+/G nanoparticles generated via the chelation of guaiacol with copper ions. Upon application to diabetic wounds, the hydrogel system’s self-healing and adhesive properties provide an effective physical barrier. Concurrently, the borate ester bonds gradually respond to H+ in the local environment, dissociating and facilitating the slow release of Cu2+/G nanoparticles, thereby reprogramming macrophages and Th17/Treg cells to concurrently regulate both innate and adaptive immune processes. This therapeutic system, characterized by its comprehensive immune regulatory effects, offers a novel platform for the management of diabetic wounds.

The online version contains supplementary material available at 10.1186/s12951-025-03987-7.