Nanocarrier Engineering Critical for Melittin's Broad Anticancer, Antiviral, and Anti-inflammatory Therapeutic Translation

Melittin, a 26-amino-acid amphipathic peptide from bee venom, exhibits broad therapeutic potential, including anticancer, antiviral, and anti-inflammatory effects. These actions stem from both direct membrane disruption and secondary intracellular stress signaling and immunomodulatory responses. However, this potent activity is intrinsically linked to significant limitations like hemolysis, nonspecific cytotoxicity, and poor systemic tolerability. The critical challenge in melittin nanomedicine is to spatially, temporally, and pharmacologically constrain its activity in vivo, necessitating advanced delivery systems.

This review synthesized current progress in melittin nanomedicine by searching peer-reviewed literature published primarily between 2020 and early 2026 in PubMed, Web of Science, and Scopus. Priority was given to studies addressing melittin biological activity, nanocarrier formulation design, toxicity modulation, and translational considerations. The authors structured their synthesis around three perspectives: the mechanistic basis of melittin action, the disease-specific logic of its reported applications, and the translational criteria distinguishing proof-of-concept platforms from development-relevant ones.

The review highlights that melittin's therapeutic effects arise from direct membrane disruption, intracellular stress signaling, and immunomodulatory responses. Nanocarrier engineering, utilizing lipidic, polymeric, inorganic, and hybrid systems, has been extensively explored to mitigate melittin's inherent toxicity. These systems aim to reduce premature systemic toxicity, improve accumulation at lesion sites, regulate peptide release kinetics, and enable active or stimulus-responsive targeting. The most decisive issues for advancing melittin therapies are not solely efficacy, but the simultaneous achievement of toxicity attenuation, precise exposure control, PK/PD interpretability, and formulation tractability within a single platform. The current evidence strongly suggests that melittin's most plausible path to clinical translation lies in delivery-controlled settings. This approach is crucial for overcoming the peptide's major limitation of potent biological activity being closely coupled to hemolysis and nonspecific cytotoxicity. > The available evidence suggests that melittin is most plausibly advanced in delivery-controlled settings, particularly where toxicity attenuation, exposure control, PK/PD interpretability, and formulation tractability can be achieved within the same platform.