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The highly immunosuppressive tumor microenvironment (TME) restricts the efficient activation of immune responses. To restore the surveillance of the immune system for robust activation, vast efforts are devoted to normalizing the TME. Here, a manganese-doped layered double hydroxide (Mn-LDH) is developed for potent anti-tumor immunity by reversing TME. Mn-LDH is synthesized via a one-step hydrothermal method. In addition to the inherent proton neutralization capacity of LDH, the introduction of manganese oxide endows LDH with an additional ability to produce oxygen. Mn-LDH effectively releases Mn2+ and Mg2+ upon exposure to TME with high levels of H+ and H2O2, which activates synthase-stimulator of interferon genes pathway and maintains the cytotoxicity of CD8+ T cells respectively, achieving a cascade-like role in innate and adaptive immunity. The locally administered Mn-LDH facilitated a "hot" network consisting of mature dendritic cells, M1-phenotype macrophages, as well as cytotoxic and helper T cells, significantly inhibiting the growth of primary and distal tumors. Moreover, the photothermal conversion capacity of Mn-LDH sparks more robust therapeutic effects in large established tumor models with a single administration and irradiation. Overall, this study guides the rational design of TME-modulating immunotherapeutics for robust immune activation, providing a clinical candidate for next-generation cancer immunotherapy.

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The efficient cytosolic delivery of the CRISPR-Cas9 machinery remains a challenge for genome editing. Herein, we performed ligand screening and identified a guanidinobenzol-rich polymer to overcome the cascade delivery barriers of CRISPR-Cas9 ribonucleoproteins (RNPs) for genome editing. RNPs were stably loaded into the polymeric nanoparticles (PGBA NPs) by their inherent affinity. The polymer facilitated rapid endosomal escape of RNPs via a dynamic multiple-step cascade process. Importantly, the incorporation of fluorescence in the polymer helps to identify the correlation between cellular uptake and editing efficiency, increasing the efficiency up to 70% from the initial 30% for the enrichment of edited cells. The PGBA NPs efficiently deliver RNPs for in vivo gene editing via both local and systemic injections and dramatically reduce PCSK9 level. These results indicate that PGBA NPs enable the cascade delivery of RNPs for genome editing, showing great promise in broadening the therapeutic potential of the CRISPR-Cas9 technique.

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Immunotherapy represents a revolutionary paradigm in cancer management, showcasing its potential to impede tumor metastasis and recurrence. Nonetheless, challenges including limited therapeutic efficacy and severe immune-related side effects are frequently encountered, especially in solid tumors. Hydrogels, a class of versatile materials featuring well-hydrated structures widely used in biomedicine, offer a promising platform for encapsulating and releasing small molecule drugs, biomacromolecules, and cells in a controlled manner. Immunomodulatory hydrogels present a unique capability for augmenting immune activation and mitigating systemic toxicity through encapsulation of multiple components and localized administration. Notably, hydrogels based on biopolymers have gained significant interest owing to their biocompatibility, environmental friendliness, and ease of production. This review delves into the recent advances in bio-based hydrogels in cancer immunotherapy and synergistic combinatorial approaches, highlighting their diverse applications. It is anticipated that this review will guide the rational design of hydrogels in the field of cancer immunotherapy, fostering clinical translation and ultimately benefiting patients.

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Insufficient activation of the stimulator of interferon genes (STING) signaling pathway and profoundly immunosuppressive microenvironment largely limits the effect of cancer immunotherapy. Herein, tumor microenvironment (TME)-responsive nanoparticles (PMM NPs) are exploited that simultaneously harness STING and Toll-like receptor 4 (TLR4) to augment STING activation via TLR4-mediated nuclear factor-kappa B signaling pathway stimulation, leading to the increased secretion of type I interferons (i.e., 4.0-fold enhancement of IFN-ß) and pro-inflammatory cytokines to promote a specific T cell immune response. Moreover, PMM NPs relieve the immunosuppression of the TME by decreasing the percentage of regulatory T cells, and polarizing M2 macrophages to the M1 type, thus creating an immune-supportive TME to unleash a cascade adaptive immune response. Combined with an anti-PD-1 antibody, synergistic efficacy is achieved in both inflamed colorectal cancer and noninflamed metastatic breast tumor models. Moreover, rechallenging tumor-free animals with homotypic cells induced complete tumor rejection, indicating the generation of systemic antitumor memory. These TME-responsive nanoparticles may open a new avenue to achieve the spatiotemporal orchestration of STING activation, providing a promising clinical candidate for next-generation cancer immunotherapy.

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Immunotherapies have shown high clinical success, however, the therapeutical efficacy is largely restrained by insufficient immune activation and an immunosuppressive microenvironment. Herein, we report tumor microenvironment (TME)-responsive manganese-enriched zinc peroxide nanoparticles (MONPs) for synergistic cancer immunotherapy by inducing the immunogenic death (ICD) of cancer cells and activating the stimulator of the interferon gene (STING) pathway. MONPs especially disassociate upon exposure to acidic tumor tissue and in situ generate •OH for the ICD effect. Moreover, Mn2+ activated the STING and synergistically induced the secretion of type I interferon and inflammatory cytokines for specific T cell responses. Meanwhile, MONPs relieved the immunosuppression of TME through decreasing Tregs and polarizing M2 macrophages to the M1 type to unleash a cascade adaptive immune response. In combination with the anti-PD-1 antibody, MONPs showed superior efficacy in inhibiting tumor growth and preventing lung metastasis. Our study demonstrates the feasibility of functional nanoparticles to amplify STING innate stimulation, showing a prominent strategy for cancer immunotherapy.

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With the development of nano drug delivery system, the treatment mode that can overcome the shortcomings of chemotherapy drugs and integrate combined therapy remains to be explored. Herein, a nano drug system was designed to achieve the combined effect of chemo/chemodynamic/photodynamic therapy on cancer. Specifically, copper clusters (CuNCs) were used as the carrier, hyaluronic acid (HA) and doxorubicin (DOX) were coupled on CuNCs and then and chlorin e6 (Ce6) was introduced to form the self-assembled HA-CuNCs@DC nanoparticles. In this system, the HA-CuNCs@DC was involved in the reaction to the acidic tumor microenvironment (TME)-release of DOX, which could not only inhibit tumor growth through chemotherapy, but enhance the generation of hydrogen peroxide. CuNCs carriers had the properties of Fenton-like activity to realize chemodynamic therapy (CDT) and oxidase-like activity to deplete intracellular glutathione (GSH). Additionally, the chemotherapy drug susceptibility increased owing to the GSH depletion and the outbreak of reactive oxygen species, indicating the enhanced CDT efficacy and amplified chemotherapy efficacy. It was also noteworthy that Ce6 could be activated by 660 nm light to produce abundant singlet oxygen for photodynamic therapy. Overall, our platform demonstrated excellent biosafety and tumor suppression capabilities. This multimodal theranostic strategy provided new insights into cancer therapy.

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Combining chemotherapy with photothermal therapy (PTT) for cancer treatment could overcome the inherent limitations of both single-modality chemotherapy and PTT. However, the obstacle of accurate drug delivery to tumor sites based on chemo-photothermal remains challenging. This article describes development of a reactive oxygen species (ROS)-responsive hyaluronic acid-based nanoparticle to overcome these drawbacks. Herein, HA-TK-MTX (HTM) was synthesized by a ROS-responsive cleaved thioketal moiety linker (TK) of methotrexate (MTX) and hyaluronic acid (HA). Through hydrophobic interaction and π-π stacking interaction, a photothermal agent IR780 was integrated into the HTM, and the IR780/HTM nanoparticles (IHTM NPs) were obtained. The IHTM NPs show high photostability, excellent photothermal performance, remarkable tumor-targeting ability, and ROS sensibility. Due to the accurate drug delivery ability and superior chemo-photothermal treatment effect of IHTM NPs, the tumor inhibition rate reached 70.95% for 4T1 tumor-bearing mice. This work serves as a precedent for the chemo-photothermal therapy of cancer by rationally designing ROS-responsive nanoparticles.

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Surgical resection of the tumor remains the preferred treatment for most solid tumors at an early stage, but surgical treatment often leads to massive bleeding and residual tumor cells. Therefore, a novel alginate/gelatin sponge combined with curcumin-loaded electrospun fibers (CFAGS) for rapid hemostasis and prevention of tumor recurrence was prepared by using an electrospinning and interpenetrating polymer network (IPN) strategy. The present results show that alginate/gelatin sponge display excellent hemostatic properties and possess more advantages than commercial gelatin hemostasis sponge. More importantly, CFAGS could control the release of curcumin, inducing curcumin to accumulate at the surgical site of the tumor, thereby inhibiting local tumor recurrence in the subcutaneous postoperative recurrence model. In addition, the sponge was safe to implant in the body and did not cause toxicity to normal tissues and organs. This approach represents a new strategy to implant a dual functional sponge at the postoperative site as an adjuvant to the surgical treatment of cancer.

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Integration of multiple therapies into one nanoplatform holds great promise to overcome the shortcomings of traditional single-modal therapy and achieve favorable antitumor efficacy. Herein, we constructed a dual receptor-targeting nanomicelle system with GSH-responsive drug release for precise fluorescence imaging and superior chemo-phototherapy of cancer. The synthetic amphiphilic hyaluronic acid derivative (FHSV) could self-assemble into nanomicelles in aqueous media. Then, paclitaxel (PTX) and photosensitizer IR780 iodide (IR780) were co-loaded into the micelles by a simple dialysis method. The resulting IR780/PTX/FHSV micelles with a particle size of 150.2 ± 6.9 nm exhibited excellent stability, GSH-responsive drug release and good photothermal/photodynamic efficacy. Once accumulated at the tumor sites, IR780/PTX/FHSV micelles efficiently entered tumor cells through receptor-mediated endocytosis and then rapidly release PTX and IR780 under GSH-rich tumor microenvironment. Upon NIR laser irradiation, IR780 produced local hyperthermia and sufficient reactive oxygen species to promote tumor cells apoptosis and necrosis. The results of in vitro and in vivo experiments consistently demonstrated that compared with single chemotherapy and phototherapy, the chemo-phototherapy could more efficiently kill tumor cells by synergistic antitumor effect. Therefore, our study provides a novel and efficient approach for multimodal treatment of malignant tumor.

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