State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Chemical Biology Center, Peking University, Beijing 100191, P. R. China.
School of Life Science, Beijing Institute of Technology, Beijing 100081, P. R. China.
Nano Lett. 2023 Apr 12;23(7):3005-3013. doi: 10.1021/acs.nanolett.3c00383. Epub 2023 Mar 29.
Mitochondria are crucial for both sonodynamic therapy and antitumor immunity. However, how to accurately damage mitochondria and meanwhile prevent the mitophagy and immune checkpoint inhibition is still a great challenge. Herein, hexyl 5-aminolevulinate hydrochloride (HAL) and 3-methyladenine (3MA) are loaded into the tumor cell-derived microparticle (X-MP), which can direct the target delivery of the prepared HAL/3MA@X-MP to the tumor cells. HAL induces the confined biosynthesis and accumulation of sonosensitizer PpIX in mitochondria, leading to the localized generation of reactive oxygen species (ROS) upon ultrasound irradiation and, thus, the efficient mitochondrial damage. Meanwhile, 3MA not only inhibits mitophagy but also down-regulates the PD-L1 expression, promoting the immunogenic cell death (ICD) while blocking the immune checkpoint recognition. The smart synergism of precise mitochondrial damage, mitophagy inhibition and antitumor immunity results in potent therapeutic efficacy without obvious side effects.
线粒体对于声动力治疗和抗肿瘤免疫都至关重要。然而，如何准确地损伤线粒体，同时防止自噬和免疫检查点抑制，仍然是一个巨大的挑战。在此，我们将盐酸 5-氨基酮戊酸己酯（HAL）和 3-甲基腺嘌呤（3MA）装载到肿瘤细胞衍生的微粒（X-MP）中，可将制备的 HAL/3MA@X-MP 靶向递送到肿瘤细胞。HAL 诱导声敏剂 PpIX 在细胞器中的受限生物合成和积累，导致超声辐照时局部产生活性氧（ROS），从而有效损伤线粒体。同时，3MA 不仅抑制自噬，还下调 PD-L1 的表达，促进免疫原性细胞死亡（ICD），同时阻断免疫检查点识别。精确的线粒体损伤、自噬抑制和抗肿瘤免疫的协同作用可产生强大的治疗效果，而无明显的副作用。
