Selective Modulation of Cutibacterium acnes Biofilms in Acne: Limitations of Conventional Therapies and Emerging Anti-Virulence Strategies.

Acne vulgaris is a multifactorial inflammatory skin disorder in which Cutibacterium acnes biofilm formation contributes to disease persistence, antimicrobial tolerance, and treatment failure. Conventional therapies primarily target bacterial viability but often fail to address biofilm-associated resilience and strain-specific virulence. Emerging strategies have therefore shifted toward the selective modulation of bacterial behavior rather than broad-spectrum eradication, with the aim of attenuating pathogenicity while minimizing disruption of the skin microbiome. This review critically evaluates selective modulation approaches targeting biofilm integrity, virulence pathways, and microbial ecology, including anti-virulence therapy, quorum-sensing inhibition, biofilm disruption, nanocarrier-based delivery systems, and microbiome-informed interventions. Preclinical studies suggest that these strategies may disrupt biofilm architecture, attenuate virulence factor expression, and potentially reduce selective pressure associated with conventional antimicrobial therapies. Approaches such as antimicrobial peptides, quorum-sensing inhibitors, and advanced delivery systems have demonstrated promising in vitro, ex vivo, and early preclinical outcomes; however, clinical evidence remains limited. Significant challenges remain, including insufficient in vivo validation, formulation instability, biofilm-associated delivery barriers, regulatory considerations, and limited long-term safety data. Overall, selective modulation represents a promising emerging framework for acne management, although its successful clinical translation will require robust clinical validation, improved disease-relevant models, and the integration of personalized strategies based on microbiome profiling and advanced delivery technologies.