Biomimetic Cascade-Responsive Natural–Synthetic Composite Hydrogel for Acne Lesion Microenvironment Modulation

Acne vulgaris is a multifactorial inflammatory skin disorder driven by abnormal follicular keratinization, microbial dysbiosis, and persistent inflammation. However, existing monotherapies often fail to simultaneously address these multiple interrelated pathological processes. Herein, a mussel-inspired, cascade-responsive natural-synthetic hydrogel (HCM) was developed for localized acne therapy through modulation of the lesion microenvironment. This hydrogel forms a three-dimensional network via dynamic Schiffbase cross-linking between oxidized hyaluronic acid (OHA) and chitosan (CS), endowing it with structural integrity, self-healing properties, and pH-responsiveness. Salicylic acid (SA) was chemically grafted onto CS chains (SA-g-CS) to mitigate local irritation and enable sustained release. Furthermore, curcumin-loaded mesoporous polydopamine nanoparticles (mPDA@Cur) were introduced to confer near-infrared-triggered photothermal antibacterial activity and antioxidant capacity. Under 808 nm near-infrared irradiation, HCM hydrogel exhibited good photothermal conversion and effectively inhibited Propionibacterium acnes (P. acnes), Staphylococcus aureus (S. aures), and Escherichia coli (E. coli), with inhibition rates as high as 97.2, 86.4, and 87.1%, respectively. In vitro studies further demonstrated favorable cytocompatibility, efficient reactive oxygen species scavenging, and enhanced fibroblast migration. In an SD rat acne model, HCM hydrogel combined with near-infrared irradiation significantly inhibited bacterial colonization, alleviated local inflammatory and tissue edema, and reduced inflammatory cell infiltration. Moreover, collagen deposition and lesion repair were promoted by it via downregulation of proinflammatory factors like IL-1β and TNF-α. Collectively, HCM integrates photothermal antibacterial activity, sustained drug delivery, antioxidative anti-inflammatory regulation, and tissue-repair capability to enable coordinated modulation of the acne lesion microenvironment. This work thus provides a promising material design strategy for localized treatment of acne and other inflammation-related skin disorders.