Melittin, the primary peptide component of bee venom, is a potent cytolytic anti-cancer peptide with established anti-tumor activity. However, practical application of melittin in oncology is hampered by its strong, nonspecific hemolytic activity and intrinsic instability. To address these shortcomings, delivery systems are used to overcome the drawbacks of melittin and facilitate its safe delivery. Yet, a recent study revealed that encapsulated melittin remains immunogenic and can act as an adjuvant to elicit a fatal antibody immune response against the delivery carrier. We discovered that substitution of l-amino acids with d-amino acids mitigates this problem: D-melittin nanoformulations induce significantly decreased immune response, resulting in excellent safety without compromising cytolytic potential. We now report the first application of D-melittin and its micellar formulations for cancer treatment. D-melittin was delivered by a pH-sensitive polymer carrier that (i) forms micellar nanoparticles at normal physiological conditions, encapsulating melittin, and (ii) dissociates at endosomal pH, restoring melittin activity. D-melittin micelles (DMM) exhibits significant cytotoxicity and induces hemolysis in a pH-dependent manner. In addition, DMM induce immunogenic cell death, revealing its potential for cancer immunotherapy. Indeed, in vivo studies demonstrated the superior safety profile of DMM over free peptide and improved efficacy at prohibiting tumor growth. Overall, we present the first application of micellar D-melittin for cancer therapy. These findings establish a new strategy for safe, systemic delivery of melittin, unlocking a potential pathway toward clinical translation for cytotoxic peptides as anti-cancer agents. which can revolutionize in vivo delivery of therapeutic peptides and peptide antigens.

蜂毒肽是蜂毒的主要肽成分，是一种有效的溶细胞性抗癌肽，具有确定的抗肿瘤活性。然而，蜂毒肽在肿瘤学中的实际应用受到其强大的非特异性溶血活性和内在不稳定性的阻碍。为了解决这些缺点，递送系统用于克服蜂毒肽的缺点并促进其安全递送。然而，最近的一项研究表明，封装的蜂毒肽仍然具有免疫原性，并且可以作为佐剂引发针对递送载体的致命抗体免疫反应。我们发现用d取代l-氨基酸-氨基酸缓解了这个问题：D-蜂毒肽纳米制剂可显着降低免疫反应，从而在不影响溶细胞潜力的情况下提供出色的安全性。我们现在报告 D-蜂毒肽及其胶束制剂在癌症治疗中的首次应用。D-蜂毒肽由一种对 pH 值敏感的聚合物载体递送，该聚合物载体 ( i ) 在正常生理条件下形成胶束纳米颗粒，包裹蜂毒肽，以及 ( ii ) 在内体 pH 下解离，恢复蜂毒肽活性。D-蜂毒肽胶束 (DMM) 表现出显着的细胞毒性并以 pH 依赖性方式诱导溶血。此外，DMM 可诱导免疫原性细胞死亡，揭示其在癌症免疫治疗方面的潜力。的确，在体内研究表明 DMM 优于游离肽的安全性，并提高了抑制肿瘤生长的功效。总体而言，我们介绍了胶束 D-蜂毒肽在癌症治疗中的首次应用。这些发现为安全、系统地递送蜂毒肽建立了新策略，为细胞毒性肽作为抗癌剂的临床转化开辟了一条潜在途径。这可以彻底改变治疗性肽和肽抗原的体内递送。