RESUMO
Ribonucleic acid (RNA) plays a pivotal role in gene regulation and protein biosynthesis. Interfering the physiological function of key RNAs to induce cell apoptosis holds great promise for cancer treatment. Many RNA-targeted anti-cancer strategies have emerged continuously. Among them, RNA interference (RNAi) has been recognized as a promising therapeutic modality for various disease treatments. Nevertheless, the primary obstacle in siRNA delivery-escaping the endosome and crossing the plasma membrane severely impedes its therapeutic potential. Thus far, a variety of nanosystems as well as carrier-free bioconjugation for siRNA delivery have been developed and employed to enhance the drug delivery and anti-tumor efficiency. Besides, the use of small molecules to target specific RNA structures and disrupt their function, along with the covalent modification of RNA, has also drawn tremendous attention recently owing to high therapeutic efficacy. In this review, we will provide an overview of recent progress in RNA-targeted cancer therapy including various siRNA delivery strategies, RNA-targeting small molecules, and newly emerged covalent RNA modification. Finally, challenges and future perspectives faced in this research field will be discussed.
Assuntos
Neoplasias , Humanos , RNA Interferente Pequeno/química , Interferência de RNA , Neoplasias/tratamento farmacológico , Neoplasias/genética , Sistemas de Liberação de Medicamentos , Regulação da Expressão GênicaRESUMO
Mitochondrial RNA (mtRNA) plays a critical role in synthesis of mitochondrial proteins. Interfering mtRNA is a highly effective way to induce cell apoptosis. Herein, we report a near-infrared (NIR) light-mediated mitochondrial RNA modification approach for long-term imaging and effective suppression of tumors. A tumor-targetable NIR fluorescent probe f-CRI consisting of a cyclic RGD peptide, a NIR fluorophore IR780, and a singlet oxygen (1 O2 )-labile furan group for RNA modification was rationally designed and synthesized. This probe was demonstrated to dominantly accumulate in cellular mitochondria and could be covalently conjugated onto mtRNA upon 808â nm irradiation resulting in prolonged retention in tumors. More notably, this covalent modification of mtRNA by f-CRI could perturb the function of mitochondria leading to remarkable tumor suppression. We thus envision that our current approach would offer a potential approach for cancer RNA interference therapeutics.
Assuntos
Neoplasias , Fotoquimioterapia , Humanos , RNA Mitocondrial/metabolismo , RNA Mitocondrial/uso terapêutico , Interferência de RNA , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Mitocôndrias/metabolismo , Corantes Fluorescentes/metabolismoRESUMO
RNA interference (RNAi) has proved to be a promising modality for disease treatment. However, the promise of conventional RNA therapeutics for clinical application is severely impeded by low delivery efficiency and susceptibility of RNAs to serum RNases. Therefore, developing advanced RNAi technology is an increasing demand for achieving precise medicine. Herein, for the first time, we propose an alkaline phosphatase (ALP)-controllable and red light-activated RNA modification (ALARM) approach for anti-tumor therapeutic application. An ALP-responsive NIR fluorogenic probe f-RCP consisting of a tumor-targeting cyclic RGD peptide, an ALP-activated photosensitizer CyOP, and an 1O2-susceptible furan module for RNA modification was rationally designed and synthesized. Studies have demonstrated that f-RCP can specifically target to liver carcinoma HepG2 cells and spontaneously emit activated NIR/photoacoustic signals upon cleavage by the ALP enzyme, allowing for sensitive detection of ALP-positive tumors. More notably, we surprisingly found that the capability of f-RCP producing singlet oxygen (1O2) under red light irradiation could be simultaneously unlocked, which can ignite the covalent cyclization reaction between furan and nucleobases of intracellular RNA molecules, leading to significant mitochondrial damage and severe apoptosis of tumor cells, in consequence realizing efficient tumor suppression. Most importantly, the potential therapeutic mechanism was first explored on the transcriptomic level. This delicate ALARM strategy may open up new insights into cancer gene therapy.
Assuntos
Fosfatase Alcalina , Neoplasias , Humanos , Luz , Corantes Fluorescentes/química , RNARESUMO
Radiotherapy (RT)-induced in situ vaccination greatly promotes the development of personalized cancer vaccines owing to the massive release of antigens initiated by tumor-localized RT eliciting the tumor-specific immune response. However, its broad application in cancer treatment is seriously impeded by poor antigen cross-presentation, low response rate, and short duration of efficacy. Herein, the tumor-antigen-capturing nanosystem dAuNPs@CpG consisting of gold nanoparticles, 3,5-cyclohexanedione (CHD), and immunoadjuvant CpG were fabricated to enhance RT-induced vaccination. Taking advantage of the specific covalent binding between CHD and sulfenic acids of antigen proteins, we show that this nanoplatform has an unexpected potential to capture the sulfenylated tumor-derived protein antigens (TDPAs) induced by RT to in situ generate a vaccination effect, achieving significant growth suppression of both primary and distant tumors in combination with PD-1 blockade. We thus believe that our work presents a powerful and effective means to improve the synergistic tumor radioimmunotherapy.
RESUMO
X-ray-induced radiodynamic therapy (RDT) that can significantly reduce radiation dose with an improved anticancer effect has emerged as an attractive and promising therapeutic modality for tumors. However, it is highly significant to develop safe and efficient radiosensitizing agents for tumor radiation therapy. Herein, we present a smart nanotheranostic system FA-Au-CH that consists of gold nanoradiosensitizers, photosensitizer chlorin e6 (Ce6), and folic acid (FA) as a folate-receptor-targeting ligand for improved tumor specificity. FA-Au-CH nanoparticles have been demonstrated to be able to simultaneously serve as radiosensitizers and RDT agents for enhanced computed tomography (CT) imaging-guided radiotherapy (RT) of colon carcinoma, owing to the strong X-ray attenuation capability of high-Z elements Au and Hf, as well as the characteristics of Hf that can transfer radiation energy to Ce6 to generate ROS from Ce6 under X-ray irradiation. The integration of RT and RDT in this study demonstrates great efficacy and offers a promising therapeutic modality for the treatment of malignant tumors.