Metal–Phenolic Network-Facilitated “Foe-to-Friend” Conversion of Melittin for Cancer Immunotherapy with Boosted Abscopal Effect

Abstract

As a naturally occurring cytolytic peptide, melittin (Mel) has strong cytolytic activity and is a potent therapeutic peptide for cancer therapy. However, the serious hemolytic activity of Mel largely impedes its clinical applications. In this work, based on the strong interactions between proteins/peptides and polyphenols, we develop a tannic acid–Fe 3+ metal–phenolic network (MPN)-based strategy that can convert Mel from foe to friend via shielding its positive charges and reducing its hemolytic activity. Besides, an immune adjuvant resiquimod (R848) is also introduced for immunostimulation, affording the final Mel- and R848-coloaded nanodrug. The Mel-caused membrane disruption can induce immunogenic cell death for immunostimulation, R848 can act as an immune adjuvant to further facilitate the immunostimulatory effect, and the tannic acid–Fe 3+ MPN-mediated Fenton reaction can produce reactive oxygen species for cancer treatment. Further experiments reveal that the nanodrug can effectively cause immunogenic cell death of tumor cells and arouse robust intratumoral and systemic antitumor immunostimulation. In the bilateral tumor-bearing mouse models, the nanodrug considerably destroys the primary tumor and also boosts the abscopal effect to ablate the distant tumor. Collectively, the MPN-facilitated “foe-to-friend” strategy may promote the practical applications of Mel and foster the development of cancer immunotherapeutics.

Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative Breast Cancer Therapy

“…Host defense peptides are emerging type of antitumor immunotherapeutic agents due to their good immunomodulatory activities. 22 They are widely expressed in complex organisms and constitute the first line of defense against infection, which is often achieved by lytic activities and the direct clearance of microbial infections. Melittin, the main effective component of bee venom, is an amphiphilic peptide with 26 amino acid residues.…”

Self-assembled metal-phenolic nanocomplexes comprised of green tea catechin for tumor-specific ferroptosis

“…These characteristics make it unsuitable for effective biomedical applications in vivo. There have been studies using EGCG chelate with a variety of metal ions to prepare nanoparticles for the treatment of diseases [ [33] , [34] , [35] , [36] , [37] ]. However, EGCG is mostly used as a delivery vector, and the synergistic therapeutic effect of EGCG in the system has not been demonstrated.…”

Homologous-targeting biomimetic nanoparticles co-loaded with melittin and a photosensitizer for the combination therapy of triple negative breast cancer

“…Many studies have shown that Mel can disrupt the integrity of phospholipid bilayers by producing transmembrane pores and thus directly cause cell death. 13–15 In addition, recent studies have shown that Mel can effectively activate antitumor immunity by promoting the release of tumor-associated antigens and the secretion of various cytokines. 16,17 Thus, Mel is considered as a promising anticancer agent.…”