An in vitro-transcribed circular RNA
targets the mitochondrial inner membrane
cardiolipin to ablate EIF4G2+/PTBP1+
Nature Cancer, 2023, 10.1038/s43018-023-00650-8
Zunyong Feng, Xuanbo Zhang, Jing Zhou, Qiang Li, Liuxi Chu, Guangfu Di, Zhengyuan Xu, Qun Chen, Ming Wang, Xiaochun Jiang, Hongping Xia, Xiaoyuan Chen
In vitro-transcribed (IVT) mRNA has arisen as a rapid method for the production of nucleic acid drugs. Here, we have constructed an oncolytic IVT mRNA that utilizes human rhinovirus type 2 (HRV2) internal ribosomal entry sites (IRESs) to selectively trigger translation in cancer cells with high expression of EIF4G2 and PTBP1. The oncolytic effect was provided by a long hGSDMDc .825 T>A/c.884 A>G-F1LCT mutant mRNA sequence with mitochondrial inner membrane cardiolipin targeting toxicity that triggers mitophagy. Utilizing the permuted intron-exon (PIE) splicing circularization strategy and lipid nanoparticle (LNP) encapsulation reduced immunogenicity of the mRNA and enabled delivery to eukaryotic cells in vivo. Engineered HRV2 IRESs-GSDMDp.D275E/E295G-F1LCT circRNA-LNPs (GSDMDENG circRNA) successfully inhibited EIF4G2+/PTBP1+ pan-adenocarcinoma xenografts growth. Importantly, in a spontaneous tumor model with abnormal EIF4G2 and PTBP1 caused by KRASG12D mutation, GSDMDENG circRNA significantly prevented the occurrence of pancreatic, lung and colon adenocarcinoma, improved the survival rate and induced persistent KRASG12D tumor antigen-specific cytotoxic T lymphocyte responses.
Ferroptosis MRI for early detection of anticancer drug-induced acute cardiac/kidney injuries.
Science advances, 9(10), eadd8539.
Zeng, F., Nijiati, S., Liu, Y., Yang, Q., Liu, X., Zhang, Q., Chen, S., Su, A., Xiong, H., Shi, C., Cai, C., Lin, Z., Chen, X., & Zhou, Z.
Ferroptosis has been realized in anticancer drug-induced acute cardiac/kidney injuries (ACI/AKI); however, molecular imaging approach to detect ferroptosis in ACI/AKI is a challenge. We report an artemisinin-based probe (Art-Gd) for contrast-enhanced magnetic resonance imaging of ferroptosis (feMRI) by exploiting the redox-active Fe(II) as a vivid chemical target. In vivo, the Art-Gd probe showed great feasibility in early diagnosis of anticancer drug-induced ACI/AKI, which was at least 24 and 48 hours earlier than the standard clinical assays for assessing ACI and AKI, respectively. Furthermore, the feMRI was able to provide imaging evidence for the different mechanisms of action of ferroptosis-targeted agents, either by blocking lipid peroxidation or depleting iron ions. This study presents a feMRI strategy with simple chemistry and robust efficacy for early evaluation of anticancer drug-induced ACI/AKI, which may shed light on the theranostics of a variety of ferroptosis-related diseases.
A hybrid semiconducting organosilica-based O2 nanoeconomizer for on-demand synergistic photothermally boosted radiotherapy
Nat Commun. 2021;12(1):523.
Tang W, Yang Z, He L, Deng L, Fathi P, Zhu S, Li L, Shen B, Wang Z, Jacobson O, Song J, Zou J, Hu P, Wang M, Mu J, Cheng Y, Ma Y, Tang L, Fan W, Chen X
The outcome of radiotherapy is significantly restricted by tumor hypoxia. To overcome this obstacle, one prevalent solution is to increase intratumoral oxygen supply. However, its effectiveness is often limited by the high metabolic demand for O2 by cancer cells. Herein, we develop a hybrid semiconducting organosilica-based O2 nanoeconomizer pHPFON-NO/O2 to combat tumor hypoxia. Our solution is twofold: first, the pHPFON-NO/O2 interacts with the acidic tumor microenvironment to release NO for endogenous O2 conservation; second, it releases O2 in response to mild photothermal effect to enable exogenous O2 infusion. Additionally, the photothermal effect can be increased to eradicate tumor residues with radioresistant properties due to other factors. This “reducing expenditure of O2 and broadening sources” strategy significantly alleviates tumor hypoxia in multiple ways, greatly enhances the efficacy of radiotherapy both in vitro and in vivo, and demonstrates the synergy between on-demand temperature-controlled photothermal and oxygen-elevated radiotherapy for complete tumor response.
Burst release of encapsulated annexin A5 in tumours boosts cytotoxic T-cell responses by blocking the phagocytosis of apoptotic cells
Nat Biomed Eng, 2020; 4: 1102-1116.
Li L, Zou J, Dai Y, Fan W, Niu G, Yang Z, Chen X
Cancer immunotherapies, particularly therapeutic vaccination, do not typically generate robust anti-tumour immune responses. Here, we show that the intratumoral burst release of the protein annexin A5 from intravenously injected hollow mesoporous nanoparticles made of diselenide-bridged organosilica generates robust anti-tumour immunity by exploiting the capacity of primary tumours to act as antigen depots. Annexin A5 blocks immunosuppressive apoptosis and promotes immunostimulatory secondary necrosis by binding to the phagocytic marker phosphatidylserine on dying tumour cells. In mice bearing large established tumours, the burst release of annexin A5 owing to diselenide-bond cleavage under the oxidizing conditions of the tumour microenvironment and the reducing intracellular conditions of tumour cells induced systemic cytotoxic T-cell responses and immunological memory associated with tumour regression and the prevention of relapse, and led to complete tumour eradication in about 50% of mice with orthotopic breast tumours. Reducing apoptosis signalling via in situ vaccination could be a versatile strategy for the generation of adaptive anti-tumour immune responses.
Management of fluorescent organic/inorganic nanohybrids for biomedical applications in the NIR-II region
Chem Soc Rev, DOI https://doi.org/10.1039/D2CS00131D
Li B, Zhao M, Lin J, Huang P, Chen X
Biomedical fluorescence imaging in the second near-infrared (NIR-II, 100–1700 nm) window provides great potential for visualizing physiological and pathological processes, owing to the reduced tissue absorption, scattering, and autofluorescence. Various types of NIR-II probes have been reported in the past decade. Among them, NIR-II organic/inorganic nanohybrids have attracted widespread attention due to their unique properties by integrating the advantages of both organic and inorganic species. Versatile organic/inorganic nanohybrids provide the possibility of realizing a combination of functions, controllable size, and multiple optical features. This tutorial review summarizes the reported organic and inorganic species in nanohybrids, and their biomedical applications in NIR-II fluorescence and lifetime imaging. Finally, the challenges and outlook of organic/inorganic nanohybrids in biomedical applications are discussed.
A nanovaccine for antigen self-presentation and immunosuppression reversal as a personalized cancer immunotherapy strategy
Nat Nanotechnol. 2022 Apr 11. doi: 10.1038/s41565-022-01098-0.
Liu C, Liu X, Xiang X, Pang X, Chen S, Zhang Y, Ren E, Zhang L, Liu X, Lv P, Wang X, Luo W, Xia N, Chen X, Liu G
The strategy of combining a vaccine with immune checkpoint inhibitors has been widely investigated in cancer management, but the complete response rate for this strategy is still unresolved. We describe a genetically engineered cell membrane nanovesicle that integrates antigen self-presentation and immunosuppression reversal (ASPIRE) for cancer immunotherapy. The ASPIRE nanovaccine is derived from recombinant adenovirus-infected dendritic cells in which specific peptide-major histocompatibility complex class I (pMHC-I), anti-PD1 antibody and B7 co-stimulatory molecules are simultaneously anchored by a programmed process. ASPIRE can markedly improve antigen delivery to lymphoid organs and generate broad-spectrum T-cell responses that eliminate established tumours. This work presents a powerful vaccine formula that can directly activate both native T cells and exhausted T cells, and suggests a general strategy for personalized cancer immunotherapy.
Artificial-enzymes-armed Bifidobacterium longum probiotics for alleviating intestinal inflammation and microbiota dysbiosis.
Nature nanotechnology, (2023) 10.1038/s41565-023-01346-x.
Cao, F., Jin, L., Gao, Y., Ding, Y., Wen, H., Qian, Z., Zhang, C., Hong, L., Yang, H., Zhang, J., Tong, Z., Wang, W., Chen, X., & Mao, Z.
Inflammatory bowel disease can be caused by the dysfunction of the intestinal mucosal barrier and dysregulation of gut microbiota. Traditional treatments use drugs to manage inflammation with possible probiotic therapy as an adjuvant. However, current standard practices often suffer from metabolic instability, limited targeting and result in unsatisfactory therapeutic outcomes. Here we report on artificial-enzyme-modified Bifidobacterium longum probiotics for reshaping a healthy immune system in inflammatory bowel disease. Probiotics can promote the targeting and retention of the biocompatible artificial enzymes to persistently scavenge elevated reactive oxygen species and alleviate inflammatory factors. The reduced inflammation caused by artificial enzymes improves bacterial viability to rapidly reshape the intestinal barrier functions and restore the gut microbiota. The therapeutic effects are demonstrated in murine and canine models and show superior outcomes to traditional clinical drugs.
Targeting the activity of T cells by membrane surface redox regulation for cancer theranostics
Nat. Nanotechnol. (2022). https://doi.org/10.1038/s41565-022-01261-7
Changrong Shi, Qianyu Zhang, Yuying Yao, Fantian Zeng, Chao Du, Sureya Nijiati, Xuejun Wen, Xinyi Zhang, Hongzhang Yang, Haoting Chen, Zhide Guo, Xianzhong Zhang, Jinhao Gao, Weisheng Guo, Xiaoyuan Chen & Zijian Zhou
T cells play a determining role in the immunomodulation and prognostic evaluation of cancer treatments relying on immune activation. While specific biomarkers determine the population and distribution of T cells in tumours, the in situ activity of T cells is less studied. Here we designed T-cell-targeting fusogenic liposomes to regulate and quantify the activity of T cells by exploiting their surface redox status as a chemical target. The T-cell-targeting fusogenic liposomes equipped with 2,2,6,6-tetramethylpiperidine (TEMP) groups neutralize reactive oxygen species protecting T cells from oxidation-induced loss of activity. Meanwhile, the production of paramagnetic 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) radicals allows magnetic resonance imaging quantification of the T cell activity. In multiple mouse models, the T-cell-targeting fusogenic liposomes led to efficient tumour inhibition and to early prediction of radiotherapy outcomes. This study uses a chemical targeting strategy to measure the in situ activity of T cells for cancer theranostics and may provide further understanding on engineering T cells for cancer treatment.
Hybrid Membrane-Decorated Prussian Blue for Effective Cancer Immunotherapy via Tumor-Associated Macrophages Polarization and Hypoxia Relief
Adv Mater, 2022, 34, 2200389
Hou L, Gongu X, Zhang JH, Yang W, Chen X
Both tumor-associated macrophages (TAMs) and hypoxia condition severely restrict the antitumor potency during cancer immunotherapy. It is essential to overcome the two issues for improving therapeutic efficacy. In this study, a hollow mesoporous Prussian blue (HMPB) nanosystem with mannose decoration and hydroxychloroquine (HCQ) adsorption is built, to form Man-HMPB/HCQ. It can facilitate cellular internalization via mannose-receptor mediated endocytosis and induce TAM polarization via iron ion/HCQ release with HMPB degradation. The hybrid macrophage and thylakoid (TK) membrane is camouflaged on the Man-HMPB/HCQ surface, denoted as TK-M@Man-HMPB/HCQ, to reduce in vivo reticuloendothelial system uptake, enhance tumor accumulation, and mitigate hypoxia. The in vivo results indicate that TK-M@Man-HMPB/HCQ notably inhibits tumor growth, induces TAM polarization, facilitates cytotoxic T lymphocytes infiltration, and alleviates hypoxia microenvironment. The rational design may provide a new pathway to modulate the tumor microenvironment for promoting cancer immunotherapy effects.
Decoy nanoparticles protect against COVID-19 by concurrently adsorbing viruses and inflammatory cytokines
Rao L, Xia S, Xu W, Tian R, Yu G, Gu C, Pan P, Meng Q-F, Cai X, Qu D, Lu L, Xie Y, Jiang S, Chen X
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the urgent need to rapidly develop therapeutic strategies for such emerging viruses without effective vaccines or drugs. Here, we report a decoy nanoparticle against COVID-19 through a powerful two-step neutralization approach: virus neutralization in the first step followed by cytokine neutralization in the second step. The nanodecoy, made by fusing cellular membrane nanovesicles derived from human monocytes and genetically engineered cells stably expressing angiotensin converting enzyme II (ACE2) receptors, possesses an antigenic exterior the same as source cells. By competing with host cells for virus binding, these nanodecoys effectively protect host cells from the infection of pseudoviruses and authentic SARS-CoV-2. Moreover, relying on abundant cytokine receptors on the surface, the nanodecoys efficiently bind and neutralize inflammatory cytokines including interleukin 6 (IL-6) and granulocyte−macrophage colony-stimulating factor (GM-CSF), and significantly suppress immune disorder and lung injury in an acute pneumonia mouse model. Our work presents a simple, safe, and robust antiviral nanotechnology for ongoing COVID-19 and future potential epidemics.
Protective Effect of Platinum Nano-antioxidant and Nitric Oxide Against Hepatic Ischemia-Reperfusion Injury
Nat Commun, 2022;13(1):2513
Mu J, Li C, Shi Y, Liu G, Zou J, Zhang D, Jiang C, Wang X, He L, Huang P, Yin Y, Chen X
Therapeutic interventions of hepatic ischemia-reperfusion injury to attenuate liver dysfunction or multiple organ failure following liver surgery and transplantation remain limited. Here we present an innovative strategy by integrating a platinum nanoantioxidant and inducible nitric oxide synthase into the zeolitic imidazolate framework-8 based hybrid nanoreactor for effective prevention of ischemia-reperfusion injury. We show that platinum nanoantioxidant can scavenge excessive reactive oxygen species at the injury site and meanwhile generate oxygen for subsequent synthesis of nitric oxide under the catalysis of nitric oxide synthase. We find that such cascade reaction successfully achieves dual protection for the liver through reactive oxygen species clearance and nitric oxide regulation, enabling reduction of oxidative stress, inhibition of macrophage activation and neutrophil recruitment, and ensuring suppression of proinflammatory cytokines. The current work establishes a proof of concept of multifunctional nanotherapeutics against ischemia-reperfusion injury, which may provide a promising intervention solution in clinical use.