Harnessing multifunctional HBc virus-like particles for safe and effective delivery of melittin in cancer therapy

To overcome the clinical limitations of melittin, a potent anticancer host defense peptide, by developing a multifunctional, virus-like particle (VLP)-based delivery system that enhances tumor targeting, immune activation, and therapeutic safety. A nanoplatform based on hepatitis B core virus-like particles (HBc VLPs) was engineered to encapsulate melittin. The design incorporated RGD peptides for improved tumor specificity, Tuftsin to promote phagocytosis, and M2pep to selectively target immunosuppressive M2 macrophages. An MMP-2-cleavable linker enabled tumor-specific activation, allowing controlled release of RGD-melittin and immune-stimulating peptides. Antitumor efficacy was evaluated in subcutaneous melanoma and lung metastasis mouse models. The multifunctional HBc VLP platform effectively protected melittin from enzymatic degradation, reduced off-target cytotoxicity, and improved tumor selectivity. It demonstrated significant tumor suppression and immune modulation in both melanoma and lung metastasis models, outperforming free melittin treatment. This study presents a versatile, multifunctional VLP-based nanoplatform for the safe and effective delivery of melittin, offering enhanced tumor targeting and immune activation. The findings support its potential for clinical translation as a novel cancer immunotherapy strategy.

为克服蜂毒肽（melittin）——一种强效抗癌宿主防御肽——的临床应用局限，本研究开发了一种基于多功能病毒样颗粒（virus-like particle, VLP）的递送系统，该系统可提升肿瘤靶向性、免疫激活能力与治疗安全性。本研究构建了基于乙肝核心病毒样颗粒（HBc VLPs）的纳米平台以包载蜂毒肽。该设计引入RGD肽以增强肿瘤特异性，添加促吞噬肽（Tuftsin）以促进吞噬作用，并搭载M2pep以选择性靶向免疫抑制性M2巨噬细胞。基质金属蛋白酶-2（MMP-2）可裂解连接子实现肿瘤特异性激活，使得RGD-蜂毒肽与免疫刺激肽得以可控释放。研究在皮下黑色素瘤与肺转移小鼠模型中评估了该平台的抗肿瘤功效。该多功能HBc VLP纳米平台可有效保护蜂毒肽免受酶解降解，降低脱靶细胞毒性，并提升肿瘤选择性。其在黑色素瘤与肺转移模型中均展现出显著的肿瘤抑制与免疫调控效果，优于游离蜂毒肽治疗组。本研究开发了一种通用型多功能VLP基纳米平台，可安全有效地递送蜂毒肽，同时提升肿瘤靶向性与免疫激活能力。研究结果表明，该平台作为新型癌症免疫治疗策略具备临床转化潜力。