A Twindrive Precise Delivery System of Platelet-Neutrophil Hybrid Membrane Regulates Macrophage Combined with CD47 Blocking for Postoperative Immunotherapy.

During wound healing after cancer surgery, platelets, neutrophils, and macrophages accumulate at the wound site and induce important pathophysiological features. Utilizing these pathophysiological features, the development of targeted delivery systems for postoperative tumor immunotherapy is an important strategy. Herein, a twindrive precise delivery system of hybrid membrane combined with CD47 blocking is developed for targeted delivery and targeted regulation to induce postoperative immunotherapy. The precise delivery system consists of IR820-modified platelet-neutrophil hybrid membranes loaded with R848 nanoparticles. Based on the pathological characteristics of platelet aggregation and neutrophil tendency caused by the wound inflammatory microenvironment after tumor surgery, the twindrive delivery system could achieve targeted delivery and targeted regulation of immune drugs to tumor sites. After precise delivery guided by fluorescence imaging, R848 is targeted to reprogram M2 macrophages into M1 macrophages, stimulate dendritic cell maturation as an adjuvant, and then activate T cell immunity. R848 polarization and CD47 blockade together enhanced the phagocytosis function of macrophages, which combined with T cell-mediated cellular immune response to finally effectively inhibit postsurgical tumor recurrence, metastasis, and prolonged survival time. It develops a targeted delivery and regulatory system for cell-specific responses to the pathophysiological features of wound healing for postoperative immunotherapy.

Macrophages-Based Biohybrid Microrobots for Breast Cancer Photothermal Immunotherapy by Inducing Pyroptosis.

Pyroptosis-based immunotherapy can escape drug resistance as well as inhibit metastasis. It is urgently required to develop a delivery platform to induce targeted tumor-specific pyroptosis for cancer immunotherapy. Herein, macrophages-based biohybrid microrobots (IDN@MC) are constructed with IR-macrophage and decitabine-loaded Metal-organic frameworks (DZNPs). The integration of fluorescence photosensitizers and pH-sensitive DZNPs endow the microrobots properties such as photothermal conversion, fluorescent navigation, targeted drug delivery, and controlled drug release. In light of the inherent tumor targeting, tumor accumulation of IDN@MC is facilitated. Due to the sustained release of decitabine from packaged DZNPs, the host macrophages are differentiated into M1 phenotypes to exert the tumor phagocytosis at the tumor site, directly transporting the therapeutic agents into cancer cells. With laser control, the rapid and durable caspase 3-cleaved gasdermin E (GSDME)-related tumor pyroptosis is achieved with combined photothermal-chemotherapy, releasing inflammatory factors such as lactate dehydrogenase and interleukin-18. Subsequently, the robust and adaptive immune response is primed with dendritic cell maturation to initiate T-cell clone expansion and modulation of the immune suppressive microenvironment, thus enhancing the tumor immunotherapy to inhibit tumor proliferation and metastasis. This macrophages-based biohybrid microrobot is an efficient strategy for breast cancer treatment to trigger photo-induced pyroptosis and augment the immune response.

Neutrophil Camouflaged Stealth Nanovehicle for Photothermal-Induced Tumor Immunotherapy by Triggering Pyroptosis.

The regulation of tumor immunosuppressive microenvironments via precise drug delivery is a promising strategy for preventing tumor recurrence and metastasis. Inspired by the stealth strategy, a stealthy nanovehicle based on neutrophil camouflage is developed to achieve precise delivery and tumor immunotherapy by triggering pyroptosis. The nanovehicle comprises anti-CD11b- and IR820-conjugated bovine serum albumin nanoparticles loaded with decitabine. Camouflaged by neutrophils, the nanovehicles achieve efficient tumor delivery by neutrophil hitchhiking owing to the biotropism of neutrophils for tumors. The fluorescent signal molecule, IR820, on the nanovehicle acts as a navigation monitor to track the precise delivery of the nanovehicle. The released decitabine upregulates gasdermin E, and laser irradiation activates caspase-3, thereby resulting in pyroptosis, which improves the system's adaptive immune response. In a triple-negative breast cancer animal model, it regulates the immunosuppressive microenvironment for effective tumor immunotherapy and induces a long-lasting and strong immune memory to prevent lung metastasis.

Hydrogel/nanoparticles-mediated cooperative combination of antiangiogenesis and immunotherapy.

Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis therapy and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. Herein, a hydrogel/nanosystem-mediated antiangiogenesis combined immunotherapy strategy was used to regulate the tumor microenvironment by the controlled release of apatinib, CD47 antibody (aCD47), and CpG. The combination of hydrogel with nanoparticles protected drug activity and maintained a long-term slow release of the drug for maximum synergistic efficacy. Apatinib promotes vascular normalization in tumors and enhances the efficacy of aCD47-based immunotherapy. The addition of immunoadjuvant CpG further enhanced antigen presentation and stimulated the anti-tumor activity of macrophages to strengthen the efficacy of antiangiogenesis combined immunotherapy. The main effector immune cells, including CD4+ T, CD8+ T, NK, and activity DCs, were significantly increased after combination treatment, while the proportion of various immunosuppressive cells decreased significantly, especially MDSCs and M2-polarized macrophages. Based on an effective systemic immune response, the hydrogel/nanoparticle-mediated cooperative combination of antiangiogenesis and immunotherapy enhanced the synergistic effect for primary tumors and prevented metastasis for tumor treatment. The biomaterial-mediated antiangiogenesis combined immunotherapy strategy is a promising strategy for effective immunotherapy. STATEMENT OF SIGNIFICANCE: Relieving immunosuppression of the tumor microenvironment is the key to restoring and rebuilding the normal anti-tumor immune defense of the body. Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. For the combination of antiangiogenesis and immunotherapy, effective drug delivery to overcome local immune tolerance and regulate the tumor microenvironment to increase therapeutic effects is an important issue. The hydrogel/nanomaterial composite system constructs a dual sustained-release system to achieve step-by-step controlled release of antiangiogenic drugs and immune immunotherapy drugs to promote cooperative combination therapy.

A photo-triggered hydrogel for bidirectional regulation with imaging visualization.

The bidirectional intelligent regulation of hydrogels is a critical challenge in on-demand functional hydrogels. In this paper, a photo-triggered hydrogel for bidirectional regulation based on IR820-α-cyclodextrin/polyethylene glycol methyl acrylate was developed. This thermosensitive hydrogel can soften from gel to sol under near-infrared irradiation based on the photothermal effect of IR820, while the hydrogel can stiffen based on the photo-crosslinking of polyethylene glycol methyl acrylate under UV laser irradiation. After implanting in vivo, the softness and stiffness of the hydrogel can be regulated in a bidirectional manner by the switching of the irradiation wavelength. Moreover, the location and status of the hydrogel was tracked in vivo by fluorescence imaging due to the fluorescence labeling of IR820. The controlled and visible hydrogel could be potentially applied to different biomedical fields for precise treatment.