Melittin (MEL) is recognized as a highly potent therapeutic peptide for treating various human diseases including cancer. However, the clinical applications of MEL are largely restricted by its severe hemolytic activity and nonspecific cytotoxicity. Here, it is found that MEL can form a stable supramolecular nanocomplex of ≈60 nm with the photosensitizer chlorin e6 (Ce6), which after hyaluronic acid (HA) coating can achieve robust, safe, and imaging‐guided tumor ablation. The as‐designed nanocomplex (denoted as MEL/Ce6@HA) shows largely reduced hemolysis and selective cytolytic activity toward cancer cells. Upon laser irradiation, the loaded photosensitive Ce6 can synergistically facilitate the membrane‐lytic efficiency of melittin and greatly increase the tumor penetration depth of the complexes in multicellular tumor spheroids. In vivo experiments reveal that MEL/Ce6@HA can realize enhanced tumor accumulation, reduced liver deposition, and rapid body clearance, which are beneficial for highly efficient and safe chemo‐photodynamic dual therapy. This work develops a unique supramolecular strategy for optimized in vivo delivery of melittin and may have implications for the development of peptide‐based theranostics.

中文翻译：

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将有毒物质转化为安全的治疗药物：蜂毒素的优化体内递送的细胞裂解肽-光敏剂组合。

蜂毒素（MEL）被认为是用于治疗包括癌症在内的各种人类疾病的高效治疗肽。但是，MEL的严重溶血活性和非特异性细胞毒性在很大程度上限制了MEL的临床应用。在这里，发现MEL可以与光敏剂二氢卟酚e6（Ce6）形成约60 nm的稳定的超分子纳米复合物，在透明质酸（HA）涂层后，该复合物可以实现坚固，安全且以成像指导的肿瘤消融。设计好的纳米复合物（称为MEL / Ce6 @ HA）显示出大大降低的溶血作用和对癌细胞的选择性细胞溶解活性。激光照射后，负载的光敏Ce6可以协同促进蜂毒素的膜分解效率，并大大增加复合物在多细胞肿瘤球体中的肿瘤穿透深度。体内实验表明，MEL / Ce6 @ HA可以实现增强的肿瘤蓄积，减少肝脏沉积和快速清除身体的功能，这对于高效，安全的化学光动力双重疗法是有益的。这项工作开发了一种独特的超分子策略，用于优化蜂毒肽的体内递送，并且可能对基于肽的治疗学理论的发展产生影响。