Zhang_2026_RSC.Adv__

This study presents a dual-precision liposomal platform (denoted Tot-Lip) rationally engineered for acne vulgaris treatment by synergistically integrating hyaluronic acid (HA)-CD44 targeting and Cutibacterium acnes (C. acnes) lipase-responsive release. Unlike conventional lipase-responsive systems with insufficient site specificity, our formulation features a soybean phosphatidylcholine/glycerol monostearate lipid bilayer decorated with HA to realize two core functions: (1) targeted accumulation at inflamed acne lesions via binding to CD44 receptors overexpressed on inflammatory cells, and (2) spatiotemporally controlled on-demand drug release triggered by C. acnes-secreted lipase. Comprehensive physicochemical characterization validated a well-defined nanostructure (67.2 nm, PDI 0.16) and favorable stimuli-responsive release profiles. In vitro assays verified strong antibiofilm activity against C. acnes, and HA surface modification markedly improved lesion-specific accumulation. Mechanistic studies using scanning electron microscopy (SEM) ultrastructural observation identified bacterial membrane disruption as the dominant bactericidal mechanism. Furthermore, Tot-Lip exerts prominent anti-inflammatory and soothing effects. This delivery system boosts therapeutic efficacy by simultaneously improving aqueous solubility, sustaining drug release, and enabling pathogen-specific activation. Collectively, this multifunctional design offers a promising approach for treating biofilm-associated skin infections through lipase-triggered precise antimicrobial delivery.