Smart Metabolism Nanovalve Reprograms Cancer Energy Homeostasis for Maximizing Photometabolism Therapy

Abstract

Better understanding of important roles of metabolic reprogramming in therapeutic resistance provides insights into advancing cancer treatment. Herein, we present a photoactive metabolic reprogramming strategy (termed as photometabolism therapy, PMT), in which photoregulation of mitochondria leads to cancer cell metabolic crisis, and consequently overcomes therapeutic resistance while improving treatment efficacy. In specific, a stimuli-responsive metabolism NanoValve is developed for improving cascade cancer therapy through blocking mitochondrial energy supply. NanoValve is composed of an onion-like architecture with a gold nanorod core, a mesoporous silica shell encapsulating photosensitizer chlorin e6 and oxygen-saturated perfluorocarbon, and cationic liposomal coating with MMP2-cleavable polyethylene glycol corona, which together initiate mitochondria-specific PMT. NanoValve selectively responds to tumor-overexpressed MMP2 and achieves size decrease and charge reversal, which consequently enhances tumor penetration, cancer cell uptake, endosome escape, and most critically, mitochondrial accumulation. Importantly, NanoValve-mediated phototherapy can strongly destruct mitochondrial energy metabolism, thereby minimizing therapy resistance. Particularly, perfluorocarbon supplies oxygen to further overcome the tumor hypoxia-associated therapeutic barrier and maximizes synergistic anticancer effects. In vivo studies show that NanoValve can effectively eliminate tumors without side effects, thereby dramatically prolonging the survival of tumor-bearing mice. Thus, NanoValve provides a modular PMT approach and has the potential of advancing the treatment of malignancy.

Recent Advances in Reprogramming Strategy of Tumor Microenvironment for Rejuvenating Photosensitizers‐Mediated Photodynamic Therapy

“…Furthermore, tumor cell metabolism can be reprogrammed to amplify PDTinduced ICD, promote dendritic cell (DC) maturation, and inhibit tumor proliferation. [59,[105][106][107][108][109] This section will focus on the strategies closely related to PDT treatment in recent years, mainly aerobic glycolysis, OXPHOS, glutamine, and cholesterol metabolism intervention strategies to amplify PDT. A more comprehensive strategies summary is shown in Table 2.…”

“…corresponding signal transduction, and cutting off the energy supply that maintains the proliferation and metastasis of malignant tumors. [106,121] It is well learned that although the "Warburg effect" [122] is generally considered to be the main pathway for tumor metabolic reprogramming, a recent study reveal that a considerable number of malignant cell lines still consume a large amount of oxygen via mitochondrial-related OXPHOS during tumorigenesis, development and metastasis, which is also one of the essential reasons for tumor hypoxia. [31,38,42,59] At present, many clinically used anti-tumor drugs, such as metformin (Met), papaverine, atorvastatin, lonidamine (LND), and tamoxifen (Tam), can reduce oxygen consumption by destroying OXPHOS to solve the problem of tumor hypoxia.…”

“…[123] Combining mitochondrial-specific nanotherapeutic drugs with PDT provides a promising metabolic reprogramming strategy. [106] For the first time, Li et al described that the photodynamic O 2saver (PDOE) strategy is not simply to regulate intracellular oxygen pressure (Figure 7a). [38] This strategy can prevent intracellu-lar O 2 consumption and down-regulate the HIF-1𝛼 expression, providing endogenous O 2 for PDT.…”

“…Mitochondria are cells' “energy factories” which are crucial in regulating energy metabolism and macromolecular biosynthesis. [ 106 ] Moreover, it was found that mitochondria are susceptible to ROS, and PDT‐based ROS production can effectively reduce its activity by blocking the biosynthesis of macromolecules, inducing apoptosis of primary tumor cells, destroying corresponding signal transduction, and cutting off the energy supply that maintains the proliferation and metastasis of malignant tumors. [ 106,121 ]…”

A Bioartificial Pancreas with “Immune Stealth” and Continuous Oxygen Supply for Islet Transplantation

“…In contrast, the oxygen concentration of the NPs-ABPP microcapsule solution rapidly increased to the upper limit of detection (20 mg L −1 ) within 43 s without reaching oxygen saturation (Figure 4C). Indeed, fluorine compounds are low polarity and exhibit excellent oxygen-carrying properties in a variety of biomedical materials, [35][36][37] making them also present great potential in improving the oxygen supply of transplanted islets. The loading of PFH/PLGA@NPs significantly enhanced the oxygen-dissolving capacity of the microcapsules, which would contribute to the survival of islet cells.…”