A Sequentially Disassembling Nanocomposite Hydrogel with Lesion-Triggered Luteolin Release for Multitarget Acne Vulgaris Therapy

Abstract Acne vulgaris (AV) remains challenging to treat due to antibiotic resistance, side effects, and the lack of topical formulations that concomitantly eradicate Cutibacterium acnes, resolve inflammation, and restore redox homeostasis. Here, we report a sequentially pH-disassembling nanocomposite hydrogel (TCL2.16‰@PQ; PQ represents poly(vinyl alcohol)/quaternized chitosan (PVA/QCS)) for comprehensive AV management, in which tannic acid/Cu2+/luteolin metal–phenolic network nanoparticles (TCL NPs) serve as both drug reservoirs and physical crosslinking nodes within PVA/QCS (PQ) matrix. The hydrogel optimally disassembles at pH 6.5, followed by TCL NP disassembly at pH 6.0, enabling microenvironment-triggered release of luteolin preferentially at the AV lesion site (5.0–7.5, 6.35 ± 1.30; healthy individuals: 4.1–5.8). This design enhances skin permeation flux by 1.5-fold compared to TCL NPs alone. Additionally, the hydrogel's shear-thinning and thixotropic properties make it easy to spread and adhere to the skin. In vitro, the hydrogel completely eradicates Cutibacterium acnes and reduces biofilm biomass by 7.6-fold at 0.2 g/mL, polarizes macrophages to the anti-inflammatory M2 phenotype, and scavenges reactive oxygen species through direct radical scavenging and upregulation of SOD/GPx/HO-1. In a murine AV model, the hydrogel achieved complete bacterial eradication and lesion resolution within 14 days, significantly outperforming a commercial metronidazole gel by concurrently reducing inflammation and restoring redox homeostasis. This work establishes a microenvironment-responsive, multitarget nanocomposite platform addressing the core pathogenic factors of AV, presenting a promising alternative to conventional therapies.