Polymersomal delivery enhances third-generation photodynamic therapy with the first white-light-activated peptide photosensitiser for melanoma

Photodynamic therapy (PDT) is an established cancer treatment, yet its clinical utility in melanoma remains restricted by poor photosensitiser delivery, light penetration, and melanin interference. Here, we report a polymersomal nanocarrier system encapsulating the peptide–photosensitiser conjugate RB-K2 as a novel strategy to overcome these barriers. The polymersomes, engineered from amphiphilic block copolymers, demonstrated enhanced stability and efficient tumour-targeted delivery. In vitro, PS-RB-K2 significantly improved cellular uptake, reactive oxygen species generation, and apoptosis induction in B16 melanoma cells compared with free RB-K2. In vivo, intratumoural administration of PS-RB-K2, combined with optimised light activation, markedly suppressed tumour growth and, in some cases, reversed progression without systemic toxicity. Mechanistic analyses confirmed that polymersomal encapsulation protected RB-K2 from degradation, enhanced intratumoural retention, and mitigated self-quenching effects. Collectively, these findings establish PS-RB-K2 as a potent third-generation PDT platform with translational potential for melanoma therapy, bridging the gap between current liposomal systems and clinically viable polymersomal drug delivery.