Multidimensional Modification and Functional Optimization of Melittin: From Natural Toxic Peptide to Safe and Effective Therapeutics

Melittin, a cationic amphipathic 26-residue peptide from bee venom, displays broad-spectrum antibacterial, antitumor and anti-inflammatory activities, yet severe hemolysis, poor cell selectivity, rapid plasma degradation and high immunogenicity hinder its clinical translation. Structural modification is a vital strategy to overcome its druggability limitations. This review systematically summarizes three mainstream modification approaches of melittin: sequence remodeling, chemical derivatization and conjugate engineering. We illustrate how these strategies tune melittin’s conformation, charge and amphiphilicity to lower toxicity and immunogenicity, improve in vivo stability, and enable targeted stimulus-responsive delivery, while unraveling its core functional sites and mechanisms. Current research gaps and future directions including combined modification, multifunctional intelligent conjugates, preclinical safety assessment and scaled production optimization are discussed, providing theoretical support for developing safe, effective melittin-based therapeutics.