Breaking Biofilm Barriers: Using CATH-ICG-Loaded Bilayer Dissolving Microneedle-Assisted Photodynamic Therapy for Deep Skin Candidiasis.

Deep skin fungal infections, particularly biofilm-associated Candida albicans (C. albicans), pose significant clinical challenges due to their resistance to conventional antifungal therapies. The stratum corneum acts as a barrier to high molecular weight drugs, limiting the penetration of systemic and topical antifungal agents. In this study, we explored a transdermal delivery system utilizing novel Cathelicidin─HcCATH-KL30 (CATH)-loaded dissolving microneedles (DMNs) for the treatment of deep dermal C. albicans biofilm infections. Preliminary evaluations demonstrated that CATH exhibited potent antifungal activity against nonfilamentous and filamentous C. albicans but was ineffective against biofilm-embedded Candida, suggesting biofilm penetration limitations. To enhance its efficacy, we integrated indocyanine green into DMNs and applied photodynamic therapy (PDT) using near-infrared (NIR) irradiation. The generated reactive oxygen species disrupted the biofilm matrix, allowing a deeper penetration of CATH for enhanced antifungal activity. Results from in vitro, ex vivo, and in vivo models demonstrated a significant reduction (∼94%) in fungal burden with CATH-ICG-DMNs following NIR irradiation, highlighting a synergistic effect. Findings of the study were mechanistically validated through qRT-PCR and propodeum iodide staining, which were in accordance with the proposed hypothesis. The current research work for the first time explored the novel antimicrobial peptide from a drug delivery platform in order to investigate its potential. This study establishes a promising microneedle-based PDT strategy for combating deep skin fungal infections, overcoming biofilm-mediated resistance and enhancing antifungal therapy efficacy.