Nanocarrier-Enabled Melittin Therapy: Mechanistic Advances, Therapeutic Applications, and Translational Challenges.

Melittin, a 26-amino-acid amphipathic peptide derived from bee venom, has attracted sustained interest in nanomedicine because of its broad anticancer, antiviral, and anti-inflammatory activities. These effects arise not only from direct membrane disruption, but also from secondary intracellular stress signaling and context-dependent immunomodulatory responses. The same mechanism, however, also underlies melittin's major limitation: potent biological activity is closely coupled to hemolysis, nonspecific cytotoxicity, and poor systemic tolerability. For this reason, the central question in melittin nanomedicine is no longer whether the peptide is bioactive, but how that activity can be spatially, temporally, and pharmacologically constrained in vivo. Nanocarrier engineering has therefore become integral to melittin development, with lipidic, polymeric, inorganic, and hybrid systems being explored to reduce premature toxicity, improve lesion-site accumulation, regulate peptide release, and enable active or stimulus-responsive targeting. In this review, we synthesize current progress from three linked perspectives: the mechanistic basis of melittin action, the disease-specific logic of its reported applications, and the translational criteria that distinguish proof-of-concept platforms from development-relevant ones. This review was prepared by searching peer-reviewed literature published primarily between 2020 and early 2026 in PubMed, Web of Science, and Scopus, with priority given to studies addressing melittin biological activity, nanocarrier formulation design, toxicity modulation, and translational considerations. Across the current literature, the most decisive issues are not efficacy alone, but the extent to which toxicity attenuation, exposure control, PK/PD interpretability, and formulation tractability can be achieved within the same platform. The available evidence suggests that melittin is most plausibly advanced in delivery-controlled settings, particularly localized, route-constrained, or selected combination-oriented applications, whereas broader systemic use still requires stronger evidence in long-term safety, pharmacological standardization, and product-level reproducibility.