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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.

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.

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.

Active targeting nanoparticles were developed to simultaneously codeliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Curcumin (Cur). In the nanoparticles (TRAIL-Cur-NPs), TRAIL was used as both active targeting ligand and therapeutic agent, and Cur could upregulate death receptors (DR4 and DR5) to increase the apoptosis-inducing effects of TRAIL. Compared with corresponding free drugs, TRAIL-Cur-NPs group showed enhanced cellular uptake, cytotoxicity and apoptosis induction effect on HCT116 colon cancer cells. In addition, in vivo anticancer studies suggested that TRAIL-Cur-NPs had superior therapeutic effect on tumors without obvious toxicity, which was mainly due to the high tumor targeting and synergistic effect of TRAIL and Cur. The synergistic mechanism of improved antitumor efficacy was proved to be upregulation of DR4 and DR5 in tumor cells induced by Cur. Thus, the prepared codelivery nanoparticles may have potential applications in colorectal cancer therapy.

Gene therapy is an efficient and promising approach to treat malignant tumors. However, protecting the nucleic acid from degradation in vivo and efficient delivering it into tumor cells remain challenges that require to be addressed before gene therapy could be applied in clinic. In this study, we prepared novel polyethyleneimine-RRRRRRRR(R8)-heparin (HPR) nanogel as an efficient gene delivery system, which consists of heparin and cell penetrating peptide R8 grafted low-molecule-weight polyethyleneimine (PEI). Due to the shielding effect of heparin, crosslinking PEI-R8 with heparin was designed to diminish the toxicity of the gene delivery system. Meanwhile, a partial of R8 peptide which located on the surface of HPR nanogel could significantly enhance the cellular uptake. The formed HPR/pDNA complex exhibited effective endolysosomal escape, resulting in a high-efficiency transfection. Furthermore, the HPR could deliver the plasmid which could transcribe human TNF-related apoptosis inducing ligand (phTRAIL), into HCT-116 cells and induce significant cell apoptosis. In addition, HPR/phTRAIL complex showed satisfactory antitumor activity in abdominal metastatic colon carcinoma model. Finally, the antitumor mechanism of HPR/phTRAIL was also explored by western blot and histological analysis. The above results suggested that the HPR nanogel could serve as a promising gene delivery system.

Tumor‐associated chronic inflammation severely restricts the efficacy of immunotherapy in cold tumors. Here, a programmable release hydrogel‐based engineering scaffold with multi‐stimulation and reactive oxygen species (ROS)‐response (PHOENIX) is demonstrated to break the chronic inflammatory balance in cold tumors to induce potent immunity. PHOENIX can undergo programmable release of resiquimod and anti‐OX40 under ROS. Resiquimod is first released, leading to antigen‐presenting cell maturation and the transformation of myeloid‐derived suppressor cells and M2 macrophages into an antitumor immune phenotype. Subsequently, anti‐OX40 is transported into the tumor microenvironment, leading to effector T‐cell activation and inhibition of Treg function. PHOENIX consequently breaks the chronic inflammation in the tumor microenvironment and leads to a potent immune response. In mice bearing subcutaneous triple‐negative breast cancer and metastasis models, PHOENIX effectively inhibited 80% and 60% of tumor growth, respectively. Moreover, PHOENIX protected 100% of the mice against TNBC tumor rechallenge by electing a robust long‐term antigen‐specific immune response. An excellent inhibition and prolonged survival in PHOENIX‐treated mice with colorectal cancer and melanoma is also observed. This work presents a potent therapeutic scaffold to improve immunotherapy efficiency, representing a generalizable and facile regimen for cold tumors. The delicate and ever‐changing nature of tumor‐associated chronic inflammation adversely affects anticancer immunity efficiency. Herein, a programmable release hydrogel‐based engineering scaffold with multi‐stimulation and reactive oxygen species (ROS)‐response (PHOENIX) is designed to break the chronic inflammatory balance in cold tumors, resulting in enhanced immunotherapy efficiency and represent a generalizable and facile regimen for cold tumor treatment.