Biomimetic Nanovesicle with Mitochondria-Synthesized Sonosensitizer and Mitophagy Inhibition for Cancer Sono-Immunotherapy.

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.

Smart Tumor-Cell-Derived Microparticles Provide On-Demand Photosensitizer Synthesis and Hypoxia Relief for Photodynamic Therapy.

Positioning essential elements of photodynamic therapy (PDT) near to mitochondria can conquer the rigorous spatiotemporal limitations of reactive oxygen species (ROS) transfer and make considerable differences in PDT. However, precise accumulation of photosensitizer (PS) and oxygen within mitochondria is still challenging. We simultaneously encapsulated hexyl 5-aminolevulinate hydrochloride (HAL) and 3-bromopyruvic acid (3BP) into microparticles collected from X-ray-irradiated tumor cells (X-MP). After systemic administration, the developed HAL/3BP@X-MP can specifically target and recognize tumor cells, where HAL induces efficient accumulation of PpIX in mitochondria via the intrinsic haem biosynthetic pathway. Meanwhile, 3BP remarkably increases the oxygen supply by inhibiting mitochondrial respiration. The accurate co-localization and prompt encounter of PpIX and oxygen produce sufficient ROS to directly disrupt mitochondria, resulting in significantly improved PDT outcomes.

Stilbene Derivatives from Photorhabdus temperata SN259 and Their Antifungal Activities against Phytopathogenic Fungi.

Chemical investigation of an insect pathogenic enterobacterium, Photorhabdus temperata SN259, led to the isolation and identification of seven metabolites, which include three new compounds, 3-hydroxy-2-isopropyl-5-phenethylphenyl carbamate, 1, 2-(1-hydroxypropan-2-yl)-5-[2-phenylethyl]benzene-1,3-diol, 2, 2-(1-hydroxypropan-2-yl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol, 3, and four known metabolites (4-7). Their structures were elucidated on the basis of MS and NMR data and by comparison with those reported previously. The activities of compounds 1-7 were evaluated against four phytopathogenic fungi (Pythium aphanidermatum, Rhizoctonia solani Kuhn, Exserohilum turcicum, and Fusarium oxysporum). In an agar medium assay, compounds 1 and 7 showed strong inhibition against P.  aphanidermatum with EC50 values of 2.8 and 2.7 µg/mL, respectively. By comparing the structure of compounds 1-7, we deduced that the acylamino group in compound 1 and the isopropyl group in compound 7 contribute to the inhibitory activity.