Follicle-Oriented “Acid-Free” Supramolecular Microcapsules Achieve Efficient Acne Therapy via Skin Microbiota Remodeling

Acne vulgaris is a multifactorial inflammatory disorder involving follicular obstruction, excessive sebum production, Cutibacterium acnes (C. acnes) colonization, immune activation, and barrier dysfunction. Current topical treatments are often limited by cutaneous irritation, antimicrobial resistance, and insufficient follicular deposition. Here, an acid-free, pH-responsive, follicle-oriented supramolecular polycystic microcapsule (SPM) particles system was developed based on a phosphatidylcholine/pterostilbene deep eutectic solvent (PC/PT DES). In this study, “SPM particles” refers to the optimized approximately 350 nm colloidal formulation, whereas “microcapsule-like” describes the compartmentalized capsule-like internal architecture observed by TEM rather than a micron-scale particle size. SPM particles showed measurable encapsulation of all three active components, storage-relevant colloidal stability, size-mediated preferential follicular deposition at an optimized particle size of approximately 350 nm, and accelerated payload release under acidic conditions. The formulation excluded conventional keratolytic acids and coencapsulated matrine, oligopeptide-32, and Centella asiatica extract to provide complementary antiacne functions. In vitro, SPM particles inhibited C. acnes, induced a membrane-damage-associated antibacterial phenotype, reduced sebocyte lipid accumulation, suppressed inflammatory cytokine release, promoted keratinocyte migration, and upregulated barrier-associated markers. In a C. acnes-induced murine acne-like model, topical SPM particles attenuated inflammatory histopathology and reduced TLR2/NF-κB-associated inflammatory signals. Exploratory 16S rRNA sequencing further showed treatment-associated changes in local skin microbiota composition, which should be interpreted as associative rather than causal evidence. In an early stage 28 day randomized, double-blind, placebo-controlled clinical evaluation, SPM particles improved selected acne-associated parameters, including erythema, lesion burden, and porphyrin-related signals, while showing favorable short-term tolerability, with no treatment-related adverse skin reactions recorded during the 28 day observation period. Overall, this PC/PT DES-based SPM particles platform provides an acid-free, follicle-oriented, multicomponent topical strategy with potential for multitarget acne intervention, while longer-term repeated-use safety remains to be established in larger clinical studies.