Lactobacillus-derived extracellular vesicles provide multi-target acne treatment by enriched proteins and skin microbiota protection

Numerous studies have highlighted the therapeutic potential of probiotics in acne. Given the complex and multifactorial nature of the disease, probiotic-based multi-target therapies may be promising. Additionally, due to their non-replicative and nanosized characteristics, probiotic-derived extracellular vesicles might provide a safer and more efficient alternative. Here, we selected three anti-acne targets-Propionibacterium acnes (P. acnes) inhibition, anti-inflammatory effects, and sebum suppression-for high-throughput screening, identifying Lactobacillus plantarum 5b4m2 with multi-target anti-acne potential. Next, we isolated 5b4m2-derived EVs (LP-EVs) and discovered that they retain the anti-acne potential of the parental bacteria while exhibiting superior skin permeability. Further studies in P. acnes-induced acne mice demonstrated that LP-EVs significantly alleviated inflammatory symptoms such as redness and swelling and effectively inhibited the colonization of P. acnes, leading to enhanced therapeutic efficacy. Then, proteomic analysis identified nine enriched proteins in LP-EVs directly associated with acne improvement, including mucus-binding protein, cell wall hydrolase, lipase, and thioredoxin. Correspondingly, pathway changes in the host were revealed by transcriptomic analysis, such as the chemokine signaling pathway, lipid metabolism, and tissue tight junctions. Moreover, LP-EVs effectively maintain the skin microbiota balance, which may also contribute to acne improvement. Collectively, our study offers a new perspective on probiotic-based multi-target strategies, which may facilitate the treatment of acne and other skin diseases in the future.