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SMA by maintaining the biological activity of IFN-α.

Macrophages were tissue-resident immune cells with dual roles: M1 subtype fights

infections via reactive oxygen species and pro-inflammatory cytokines, while M2
subtype promotes tissue repair through anti-inflammatory factors and ECM remodeling.

Their plasticity maked them key targets for treating chronic inflammation and cancer. 103

In diabetic wounds, the abnormal polarization of macrophages has become an important

barrier for wound repair. This problem arised from the chronic inflammatory

environment induced by hyperglycemia and obesity, which perpetuates the activation

of M1 macrophages and hinders tissue regeneration. 104 Reduced macrophage secretion

of growth factors (TGF-β1, PDGF-BB) and pro-inflammatory cytokines (IL-6, TNF-α)

created an optimal healing environment: keratinocytes differentiate properly,

fibroblasts deposit balanced collagen, and new blood vessels form without leakage,

resulting in faster wound closure with minimal scarring. Macrophages were highly

heterogeneous and exhibit a variety of functions and phenotypes. 105-108 Diabetic wounds

were characterized by prolonged inflammatory phase and difficulty in healing due to

accumulation of M1 macrophages in the wound. Therefore, dressings with macrophage
heterogeneity regulation have great potential in clinical applications to promote diabetic

wound healing. However, precise conversion of M1 into M2 macrophages by simple

and biosafe methods remains a great challenge. Deng Li et al. 109 developed a reactive

oxygen species/glucose-responsive hydrogel coupled to a chemokine aptamer

encapsulating mannose-modified lipid nanoparticles (mLNPs) loaded with ADAM17

siRN. This hydrogel enhanced macrophage recruitment by enriching endogenous

chemokines. In addition, it was responsive to the pathological microenvironment with

dynamic release of mLNPs to deliver targeted sirnas to macrophages. ADAM17

siR@mLNPs treatment significantly enhanced the hyperphagia through the MerTK-

Rac1 pathway and glycolytic reprogramming, thereby initiating the resolution of

inflammation and tissue repair. Wei Yang et al. 110 developed a natural hydrogel capable

of modulating macrophage heterogeneity to promote angiogenesis and diabetic wound

healing. This hydrogel exhibited excellent bioadhesion, antibacterial performance, and

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