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

Abstract

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 5aminolevulinate 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.

Biomimetic Nano-Drug Delivery System: An Emerging Platform for Promoting Tumor Treatment

“… 213 Irradiated tumor cell-derived microparticles have also been shown to enhance drug particle targeting. 214 Surface modification methods, similar to natural CMs, also apply to EVs to enhance their precise targeting and tumor penetration ability. A specific anti-glioma-targeted delivery system, using angiopep-2 and TAT peptide-functionalized small extracellular vesicles, efficiently crosses the blood-brain barrier, targets gliomas, penetrates tumors, and achieves precise glioma chemotherapy, minimizing drug-related toxicities.…”

Nanoplatform-Mediated Autophagy Regulation and Combined Anti-Tumor Therapy for Resistant Tumors

“…Meanwhile, 3-MA inhibited the NF-κB pathway in tumor cells, downregulated the expression of PD-L1, and jointly activated the anti-tumor immune response, significantly improving the therapeutic efficacy in breast cancer. 128 …”

“…What’s more, research also indicated that the same signaling pathway can play opposite roles in different tumor-related cells. Inhibiting the NF-κB signaling pathway in tumor cells through 3-MA can downregulate PDL1 expression, 128 improving the efficacy of immunotherapy, while CQ reprograms TAM by activating the NF-κB signaling pathway in macrophages and resets them to a pro-inflammatory phenotype. 132 It’s possible because the same protein mediates different signaling pathways in tumor cells or immune cells, and the changes in cellular responses caused by inhibiting different stages of autophagy may also play a role.…”

“…Meanwhile, 3-MA inhibited the NF-κB pathway in tumor cells, downregulated the expression of PD-L1, and jointly activated the anti-tumor immune response, significantly improving the therapeutic efficacy in breast cancer. 128 In addition, many researchers have discovered that inhibiting autophagy can not only regulate anti-tumor immune responses by affecting tumor cells, but also affect immune cells in the tumor microenvironment to promote anti-tumor immune response, combining with anti-tumor drugs can synergistically significantly enhance immunotherapy efficacy: (1) Combination with chemotherapy prodrug: Yang X et al co-delivered the chemotherapy prodrug Pt(IV) and CQ through Pt(IV)/ CQ/PFH NPs-D PPA-1 nanoparticles, 129 to promote cell apoptosis; (2) Combination with chemokinetic therapeutic drugs: researchers co-delivered iron, artemisinin (ART) 130 or Fe, MIL88 with CQ, 131 through L-FHM@A-CQ or CQ-dual MOF nanoparticles, generating excessive ROS through the chemokinetic drugs, while inhibiting protective autophagy; (3) Combination with photoimmunotherapy drugs: Chen M et al synthesized CQ/IR780-Mil nanoparticles to co-deliver the photoimmunogenic death inducer IR 780 and CQ. IR780 is activated by light to produce phototoxicity and induce ICD while inhibiting the protective autophagy subsequently.…”

Nanomaterials augmented bioeffects of ultrasound in cancer immunotherapy

“…SDT of tumors mainly relies on ROS-induced mitochondrial damage, while mitochondrial autophagy neutralizes the SDT effect. To solve this problem, Zuo et al [ 166 ] developed a bionic nanovesicle HAL/3MA@X-MP. Through the tumor homologous targeting ability of the nanovesicles, HAL and 3MA were co-delivered to tumor cells.…”