Nanoarchitectonics of melittin-based polymersomes inducing lysosomal rupture for anticancer therapy

초록

Melittin, a 26-amino-acid peptide derived from honeybee venom, exhibits potent anticancer activity but is limited by non-specific hemolysis and rapid in vivo clearance. To overcome these challenges, amphiphilic PLLA-Cys-melittin was synthesized by conjugating hydrophobic polylactic acid (PLLA) with hydrophilic melittin via a disulfide bond, forming self-assembling polymersomes in aqueous solutions. To enhance delivery efficiency and reduce hemolysis, the cationic polymersomes were coated with anionic human serum albumin (HSA), producing HSA-coated PLLA-Cys-melittin nanoparticles (PMH NPs). This HSA coating facilitates SPARC (Secreted Protein, Acidic and Rich in Cysteine)-mediated internalization into cancer cells, thereby ensuring targeted and safer delivery. Once internalized, the HSA layer dissociates under glutathione-rich conditions in lysosomes and the cytosol, releasing melittin and leading to cancer cell death. Cellular uptake studies revealed specific internalization and increased toxicity of PMH NPs in SPARC-positive cells, along with reduced hemolysis. In vivo experiments demonstrated a significant reduction in tumor volume in PMH NP-treated groups, without affecting body weight or causing major organ toxicity. Collectively, these findings suggest that PMH NPs offer a promising platform for the safe and effective delivery of melittin, providing a viable strategy for cancer therapy.

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