Journal Article

ANG‐Modified Liposomes Coloaded With α‐Melittin and Resveratrol Induce Apoptosis and Pyroptosis in Glioblastoma Cells by Impeding Wnt/β‐Catenin Signaling

Xu, Ye, Liu, Wensen, Geng, Xiao, Dong, Mingxin, Xin, Wenwen, Zhang, Hai‐Qian, Liu, Ziwei, Xu, Na, Sun, Chengbiao, Yu, Kaikai, Wang, Yan

2025

Overview

Main Problem Glioblastoma (GB) is one of the most prevalent and devastating types of brain cancer for which efficient treatments are currently lacking because of limitations such as antitumor efficacy, brain delivery, tumor selectivity, and drug resistance. A promising strategy to overcome these obstacles is developing anticancer agents that can be delivered to GB tissues to inhibit tumors with low toxicity to normal brain tissue. Methods We developed liposomes encapsulating resveratrol (RES), a polyphenolic compound, and α‐melittin (α‐MEL), which is composed of melittin conjugated with an amphiphilic α‐helical peptide at its N‐terminus. RES‐, α‐MEL‐, and α‐MEL‐RES‐loaded liposomes (Lips) were modified with Angiopep‐2 (ANG). The effects of the above liposomes on GB cells were assessed, and the possible mechanisms were analyzed. Results ANG‐modified α‐MEL‐RES‐Lips treatment facilitated the passage of these agents through the blood–brain barrier (BBB), increased tumor targeting, and significantly reduced α‐MEL‐associated hemolysis. The combined management of α‐MEL with RES impeded GB cell growth and prolonged the lifespan of GB tumor‐bearing model mice. α‐MEL‐RES‐Lips treatment triggered GB cell apoptosis and induced pyroptosis‐associated protein expressions of gasdermin‐D (GSDMD), gasdermin E (GSDME), cleaved caspase 3, and NLR family pyrin domain containing 3 (NLRP3), and inhibited epithelial–mesenchymal transition (EMT) by modulating the Wnt/β‐catenin signaling pathway. Conclusion ANG‐modified α‐MEL‐RES‐Lips might be a potential nanosystem for GB therapy, and polyphenolic compounds combined with antimicrobial peptides may promote the induction of apoptosis, pyroptosis, and the apoptosis–pyroptosis switch in GB. ANG‐modified liposomes encapsulating α‐melittin and resveratrol increase their blood–brain barrier penetration and GB cell selectivity. The combined treatment of α‐melittin with resveratrol markedly facilitates apoptosis and pyroptosis, and promotes the apoptosis–pyroptosis switch in the GB cells via downregulating the Wnt/β‐catenin signaling.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Amino acids / Animal models / Animals / Antimicrobial peptides / Antineoplastic drugs / Antitumor activity / Apoptosis / Apoptosis - drug effects / Apoptosis - physiology / Biotechnology / Blood-brain barrier / Brain Neoplasms - drug therapy / Brain Neoplasms - metabolism / Brain Neoplasms - pathology / Brain tumors / Caspase-3 / Catenin / Cell cycle / Cell growth / Cell Line, Tumor / Cholesterol / combination therapy / Drug resistance / Fourier transforms / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma - metabolism / Glioblastoma - pathology / Glioblastoma cells / Glioma / Humans / Life span / Liposomes / Male / Melitten - administration & dosage / Melitten - pharmacology / Membranes / Metabolism / Mice / Mice, Nude / Original / Peptides / Peptides - administration & dosage / Permeability / Polyethylene glycol / Polyphenols / Pyrin protein / Pyroptosis / Pyroptosis - drug effects / Pyroptosis - physiology / Reagents / Resveratrol / Resveratrol - administration & dosage / Resveratrol - pharmacology / Signal transduction / Toxicity / Wnt protein / Wnt Signaling Pathway - drug effects / Wnt Signaling Pathway - physiology / Wnt/β‐catenin signaling pathway / α‐Melittin