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Efficient cancer immunotherapy depends on selective targeting of high bioactivity therapeutic agents to the tumours. However, delivering exogenous medication might prove difficult in clinical practice. Here we report a cooperative Nano-CRISPR scaffold (Nano-CD) that utilizes a specific sgRNA, selected from a functional screen for triggering endogenous GDSME expression, while releasing cisplatin to initiate immunologic cell death. Mechanistically, cascade-amplification of the antitumor immune response is prompted by the adjuvantic properties of the lytic intracellular content and enhanced by the heightened GDSME expression, resulting in pyroptosis and the release of tumor associated antigens. Neither of the single components provide efficient tumour control, while tumor growth is efficiently inhibited in primary and recurrent melanomas due to the combinatorial effect of cisplatin and self-supplied GSDME. Moreover, Nano-CD in combination with checkpoint blockade creates durable immune memory and strong systemic anti-tumor immune response, leading to disease relapse prevention, lung metastasis inhibition and increased survival in mouse melanomas. Taken together, our therapeutic approach utilizes CRISPR-technology to enable cell-intrinsic protein expression for immunotherapy, using GDSME as prototypic immune modulator. This nanoplatform thus can be applied to modulate further immunological processes for therapeutic benefit. Delivery of immune therapy drugs to tumours might be hampered by their limited bioavailability and the difficulty of targeting complex exogenous compounds. Here authors trigger immunologic cell death, via activating tumour-cell-intrinsic pathways via CRISPR-based nanotechnology to enable efficient anti-tumour immune response in mouse models of melanoma.

Over the past decade, numerous studies have attempted to enhance the effectiveness of radiotherapy (external beam radiotherapy and internal radioisotope therapy) for cancer treatment. However, the low radiation absorption coefficient and radiation resistance of tumors remain major critical challenges for radiotherapy in the clinic. With the development of nanomedicine, nanomaterials in combination with radiotherapy offer the possibility to improve the efficiency of radiotherapy in tumors. Nanomaterials act not only as radiosensitizers to enhance radiation energy, but also as nanocarriers to deliver therapeutic units in combating radiation resistance. In this review, we discuss opportunities for a synergistic cancer therapy by combining radiotherapy based on nanomaterials designed for chemotherapy, photodynamic therapy, photothermal therapy, gas therapy, genetic therapy, and immunotherapy. We highlight how nanomaterials can be utilized to amplify antitumor radiation responses and describe cooperative enhancement interactions among these synergistic therapies. Moreover, the potential challenges and future prospects of radio-based nanomedicine to maximize their synergistic efficiency for cancer treatment are identified.

Nanocarriers with positive surface charges are known for their toxicity which has limited their clinical appli- cations. The mechanism underlying their toxicity, such as the induction of inflammatory response, remains largely unknown. In the present study we found that injection of cationic nanocarriers, including cationic liposomes, PEI, and chitosan, led to the rapid appearance of necrotic cells. Cell necrosis induced by cationic nanocarriers is dependent on their positive surface charges, but does not require RIP1 and Mlkl. Instead, intracellular Na^＋ overload was found to accompany the cell death. Depletion of Na^＋ in culture medium or pretreatment of cells with the Na^＋/K^＋- ATPase cation-binding site inhibitor ouabain, protected cells from cell necrosis. Moreover, treatment with cationic nanocarriers inhibited Na^＋/K^＋-ATPase activity both in vitro and in vivo. The computational simulation showed that cationic carriers could interact with cation-binding site of Na^＋/K^＋-ATPase. Mice pretreated with a small dose of ouabain showed improved survival after injection of a lethal dose of cationic nanocarriers. Further analyses suggest that cell necrosis induced by cationic nanocarriers and the resulting leakage of mitochondrial DNA could trigger severe inflammation in vivo, which is mediated by a pathway involving TLR9 and MyD88 signaling. Taken together, our results reveal a novel mechanism whereby cationic nanocarriers induce acute cell necrosis through the interaction with Na^＋/K^＋-ATPase, with the subsequent exposure of mitochondrial damage-associated molecular patterns as a key event that mediates the inflammatory responses. Our study has important implications for evaluating the biocompatibility of nanocarriers and designing better and safer ones for drug delivery.

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (CRISPR/Cas9) systems initiate a revolution in genome editing, which have a significant potential for treating cancer. A significant amount of research has been conducted regarding genetic modification using CRISPR/Cas9 systems, and 33 clinical trials using ex vivo or in vivo CRISPR/Cas9 gene editing techniques have been carried out to treat cancer. Despite its potential advantages, the main obstacle to convert CRISPR/Cas9 technology into clinical genome editing applications is the safe and efficient transport of genetic material owing to various extra‐ and intracellular biological hurdles. We outline the characteristics of three forms of CRISPR/Cas9 cargos, plasmids, mRNA/sgRNA, and ribonucleoprotein (RNP) complexes in this review. The recent in vivo nanotechnology‐based delivery techniques for these three categories to treat cancer are then reviewed. In the end, we outline the prerequisites for effective and secure in vivo CRISPR/Cas9 delivery in clinical contexts and discuss challenges with current nanocarriers. This review offers a thorough overview of the CRISPR/Cas9 nano‐delivery system for the treatment of cancer, serving as a resource for the design and building of CRISPR/Cas9 delivery systems and offering fresh perspectives on the treatment of tumors. Schematic of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) system and its nanotechnology delivery methods. The CRISPR/Cas9 system can be delivered in the forms of DNA, mRNA/sgRNA, or ribonucleoprotein (RNP). The gene editing tools based on CRISPR/Cas9 include CRISPR knockout (CRISPR KO), CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa). Lipid nanoparticles, polymers, inorganic compounds, polypeptide, dendrimers, and extracellular vesicles are the most often employed substances for CRISPR/Cas9 system delivery. Created with Biorender.com.

To develop injectable formulation and improve the stability of curcumin (Cur), Cur was encapsulated into monomethyl poly (ethylene glycol)-poly (ε-caprolactone)-poly (trimethylene carbonate) (MPEG-P(CL- co -TMC)) micelles through a single-step solid dispersion method. The obtained Cur micelles had a small particle size of 27.6 ± 0.7 nm with polydisperse index (PDI) of 0.11 ± 0.05, drug loading of 14.07 ± 0.94% and encapsulation efficiency of 96.08 ± 3.23%. Both free Cur and Cur micelles efficiently suppressed growth of CT26 colon carcinoma cells in vitro . The results of in vitro anticancer studies confirmed that apoptosis induction and cellular uptake on CT26 cells had completely increased in Cur micelles compared with free Cur. Besides, Cur micelles were more effective in suppressing the tumor growth of subcutaneous CT26 colon in vivo and the mechanisms included the inhibition of tumor proliferation and angiogenesis and increased apoptosis of tumor cells. Furthermore, few side effects were found in Cur micelles. Overall, our findings suggested that Cur micelles could be a stabilized aqueous formulation for intravenous application with improved antitumor activity, which may be a potential treatment strategy for colon cancer in the future.

With the development of nanosystems, they are gradually utilized to ameliorate diverse cancer therapies. Specifically for immunotherapy, most nanosystems are elaborately designed to initiate the self‐sustaining “cancer immunity cycle (CIC)” to elicit the immune response. However, owing to the highly complex circulatory environment, nanosystems may face issues like nonspecific nanoparticle uptake and rapid clearance, leaving enormous room for advancement. For employing the biomimetic design in nanosystems, biomimetic nanosystems based on cell membranes (BNCMs) inherit various functional molecules from source cells, permitting precise tumor targeting, enhancing blood circulation, and conferring more desired functionality for a more robust immune response. To take full advantage of the BNCMs, understanding their functions in cancer immunotherapy is essential. In this review, the unique properties of BNCMs derived from various cells and main preparation strategies are introduced. Subsequently, the recent advances of BNCMs for improving cancer immunotherapy are discussed from the aspects of their roles in particular stages of the CIC, and the working mechanisms of the outer cell membranes are highlighted. Finally, along with the analysis of existing bottlenecks for clinical translation, some suggestions for the future development of BNCMs are put forward. This review represents recent advances in biomimetic nanosystems based on cell membranes for promoting cancer immunotherapy from aspects of their roles in particular stages of the “cancer immunity cycle,” which includes (1) promoting tumor cells to release TAAs through the ICD; (2) increasing APCs presentation; (3) regulating T cells, including enhancing activation and inhibiting exhaustion; 4) modulating the immunosuppressive TME.

Rapid growth in nanoparticles (NPs) as delivery systems holds vast promise to promote therapeutic approaches for cancer treatment. Presently, a diverse array of NPs with unique properties have been developed to overcome different challenges and to achieve sophisticated delivery routes for enhancement of a series of therapies. Inspiring advances have been achieved in the field of cancer therapy using NPs. In this review, we aim to summarize the up‐to‐date progression of NPs for addressing various challenges, and expect to elicit novel and potential opportunities alternatively. We first introduce different sorts of NP technologies, illustrate their mechanisms, and present their applications. Then, the achievements made by NPs to break obstacles in delivering cargoes to specific sites through particular routes are highlighted, including long‐circulation, tumor targeting, responsive release, and subcellular localization. We subsequently retrospect recent research of NPs in different cancer treatments from single therapy, like chemotherapy, to combination therapy, like chemoradiotherapy, and to integrative therapy. Finally, the challenges and perspectives of NPs in cancer therapy, and their potential impact on the field of oncology are discussed. We believe this review can offer a deeper understanding of the challenges and opportunities of NPs for cancer therapy. Rapid growth in nanoparticles as delivery systems holds massive promise to improve therapeutic approaches for cancer treatment through overcoming different challenges and achieving sophisticated delivery routes. Created by Microsoft PowerPoint 2019, image.baidu.com and Adobe Photoshop CC 2019.

Colorectal cancer (CRC) ranks among the leading causes of cancer‐related dea ths worldwide, and the rising incidence and mortality of CRC underscores the urgent need for better understanding and management strategies. Icaritin (ICA) is the metabolites of icariin, a natural flavonoid glycoside compound derived from the stems and leaves of Epimedium. It has broad spectrum antitumor activity and inhibits the proliferation, migration, and invasion of CRC cells, and causes S phase cell cycle arrest. It exerts its antitumor effects against CRC through repressing autophagy to promote CRC cell apoptosis via interfering the HSP90‐TXNDC9 interactions. The safety and efficacy of ICA are also affirmed in a mouse xenograft model. Additionally, to test whether ICA exerts synergistic effects with low‐temperature photothermal therapy (LTPTT), a novel nanodrug delivery system, employing SiO2 nanocarriers, is designed aiming to load ICA with photothermal materials polydopamine (PDA), and folic acid (FA). This SiO2/Ica‐PDA‐FA multifunctional nanocomposite actively targets tumor tissues through the high affinity of FA for cancer cells. Once internalized, the acidic intracellular environment triggers the controlled release of ICA, inhibiting HSP90‐TXNDC9 interactions. By LTPTT and ICA drug therapy under near‐infrared illumination, a dual synergistic antitumor effect is achieved, holding promise for enhancing therapeutic outcomes in CRC treatment. Icaritin demonstrates broad antitumor effects by inhibiting colorectal cancer (CRC) cell proliferation, migration, invasion, and causing cell cycle arrest. It induces apoptosis by repressing autophagic flux through disrupting HSP90‐TXNDC9 interactions. Proven safe and effective in mouse models, icaritin is also integrated with low‐temperature photothermal therapy using SiO₂/PDA/FA nanocarriers for targeted, synergistic CRC treatment under near‐infrared light.

Immune checkpoint blockade (ICB) is an attractive option in cancer therapy, but its efficacy is still less than expected due to the transient and incomplete blocking and the low responsiveness. Herein, an unprecedented programmable unlocking nano‐matryoshka‐CRISPR system (PUN) targeting programmed cell death ligand 1 (PD‐L1) and protein tyrosine phosphatase N2 (PTPN2) is fabricated for permanent and complete and highly responsive immunotherapy. While PUN is inert at normal physiological conditions, enzyme‐abundant tumor microenvironment and preternatural intracellular oxidative stress sequentially trigger programmable unlocking of PUN to realize a nano‐matryoshka‐like release of CRISPR/Cas9. The successful nucleus localization of CRISPR/Cas9 ensures the highly efficient disruption of PD‐L1 and PTPN2 to unleash cascade amplified adaptive immune response via revoking the immune checkpoint effect. PD‐L1 downregulation in tumor cells not only disrupts PD‐1/PD‐L1 interaction to attenuate the immunosurveillance evasion but also spurs potent immune T cell responses to enhance adaptive immunity. Synchronously, inhibition of JAK/STAT pathway is relieved by deleting PTPN2, which promotes tumor susceptibility to CD8+ T cells depending on IFN‐γ, thus further amplifying adaptive immune responses. Combining these advances together, PUN exhibits optimal antitumor efficiency and long‐term immune memory with negligible toxicity, which provides a promising alternative to current ICB therapy. Programmable unlocking nano‐matryoshka‐CRISPR (PUN) possesses multistage sensitive properties and exhibits excellent performances, including prolonged blood circulation, precise tumor recognition, deep tumor penetration, robust lysosomal escape, and effective transfection. With the precise control of CRISPR/Cas9 activation, PUN realizes complete and thorough intracellular disruption of PD‐L1 and PTPN2, thus eliciting cascade amplified adaptive immune response to boost antitumor immune effects.

Background Photothermal therapy (PTT) is taken as a promising strategy for cancer therapy, however, its applicability is hampered by cellular thermoresistance of heat shock response and insufficient accumulation of photothermal transduction agents in the tumor region. In consideration of those limitations, a multifunctional “Golden Cicada” nanoplatform (MGCN) with efficient gene delivery ability and excellent photothermal effects is constructed, overcoming the thermoresistance of tumor cells and improving the accumulation of indocyanine green (ICG). Results Down-regulation of heat shock protein 70 (HSP70) makes tumor cells more susceptible to PTT, and a better therapeutic effect is achieved through such cascade augmented synergistic effects. MGCN has attractive features with prolonged circulation in blood, dual-targeting capability of CD44 and sialic acid (SA) receptors, and agile responsiveness of enzyme achieving size and charge double-variable transformation. It proves that, on the one hand, MGCN performs excellent capability for HSP70-shRNA delivery, resulting in breaking the cellular thermoresistance mechanism, on the other hand, ICG enriches in tumor site specifically and possesses a great thermal property to promoted PTT. Conclusions In short, MGCN breaks the protective mechanism of cellular heat stress response by downregulating the expression of HSP70 proteins and significantly augments synergistic effects of photothermal/gene therapy via cascade augmented synergistic effects.