Abstract Macrophages, capable of both direct killing and antigen presentation, are crucial for the interplay between innate and adaptive immunity. However, strategies mainly focus on polarizing tumor‐associated macrophages (TAMs) to M1 phenotype, while overlooking the inefficient antigen cross‐presentation due to hyperactive hydrolytic protease within lysosomes which leads to antigen degradation. In light of the significant influence of reactive oxygen species (ROS) on TAMs' polarization and the inhibition of phagosomal proteolysis, a novel nanosystem termed OVA‐Fe‐GA (OFG) is engineered, drawing inspiration from the NOX2 enzyme's role. OFG integrates ovalbumin (OVA) and a network composed of Fe‐gallic acid (GA), emulating the NOX2 enzyme's sequential ROS generation process (“O 2 to O 2 •− to H 2 O 2 /•OH”). Furthermore, it elucidates a biological mechanism that augments antigen cross‐presentation by suppressing the expression of cysteine proteases. OFG restores the innate anti‐tumor functionality of TAMs and significantly amplifies their antigen cross‐presentation (4.5‐fold compared to the PBS control group) in B16‐OVA tumor‐bearing mice. Notably, the infiltration and activity of intratumoral CD8 + T cells are enhanced, indicating an adaptive immune response. Moreover, OFG exhibits excellent photothermal properties, thereby fostering a system antitumor immune response. This study provides a promising strategy for initiating both innate and adaptive immunity via TAMs activation.
Reactive oxygen species (ROS)-responsive nanomedicine has been extensively developed to improve the therapeutic effects while reducing the systemic toxicity. ROS, as important biological metabolites and signaling molecules, are known to overexpress in most of tumors and inflammations. Among various ROS-sensitive moieties, phenylborate ester (PBAE) with easy modifiable structure and excellent biocompatibility, represents one of the most ROS-sensitive structures. To harness it as a switch, the past several years had witnessed a booming of ROS-sensitive PBAE-based nanomedicine for various medical purposes. Much of the efforts were devoted to exploiting the potential in the management of antitumor and anti-inflammation. This review first summarizes the design strategies of PBAE in the construction of nanomedicine, with PBAE acting as not only the ROS-responsive unit, but also the roles of hydrophobic backbone or bridging segment in the macromolecular structures. The ROS-responsive mechanisms are then briefly discussed. Afterward, we focus on the introduction of the state-of-the-art research on ROS-responsive PBAE-based nanomedicine for antitumor and anti-inflammation applications. The conclusion and future perspectives of ROS-responsive nanomedicine are also provided.
Vaccines are a promising immunotherapy that awakens the human immune system to inhibit and eliminate cancer with fewer side effects compared with traditional radiotherapy and chemotherapy. Although cancer vaccines have shown some efficacy, there are still troublesome bottlenecks to expand their benefits in the clinic, including weak immune effects and limited therapeutic outcomes. In the past few years, in addition to neoantigen screening, a main branch of the efforts has been devoted to promoting the lymph nodes (LNs) targeting of cancer vaccines and the cross-presentation of antigens by dendritic cells (DCs), two cardinal stages in effective initiation of the immune response. Especially, nanomaterials have shown hopeful biomedical applications in the improvement of vaccine effectiveness. This Review briefly outlines the possible mechanisms by which nanoparticle properties affect LN targeting and antigen cross-presentation and then gives an overview of state-of-the-art advances in improving these biological outcomes with nanotechnology.
Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a "lactate treatment plant" (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNPCu). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (H2O2), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors.
Cell membrane coated nanoparticles have been designed for inflammation and cancer therapy. An array of cell membranes from cell library were extracted and leveraged to coat a variety of nanoparticles for different diseases.
Antigen self-assembly nanovaccines advance the minimalist design of therapeutic cancer vaccines, but the issue of inefficient cross-presentation has not yet been fully addressed. Herein, we report a unique approach by combining the concepts of "antigen multi-copy display" and "calcium carbonate (CaCO3) biomineralization" to increase cross-presentation. Based on this strategy, we successfully construct sub-100 nm biomineralized antigen nanosponges (BANSs) with high CaCO3 loading (38.13 wt%) and antigen density (61.87%). BANSs can be effectively uptaken by immature antigen-presenting cells (APCs) in the lymph node upon subcutaneous injection. Achieving efficient spatiotemporal coordination of antigen cross-presentation and immune effects, BANSs induce the production of CD4+ T helper cells and cytotoxic T lymphocytes, resulting in effective tumor growth inhibition. BANSs combined with anti-PD-1 antibodies synergistically enhance anti-tumor immunity and reverse the tumor immunosuppressive microenvironment. Overall, this CaCO3 powder-mediated biomineralization of antigen nanosponges offer a robust and safe strategy for cancer immunotherapy.
Tumor immunotherapy, including monoclonal antibody of immune checkpoint blockade, therapeutic antibody,cancer vaccine and cell therapy, etc., is to restart and maintain the tumor immune cycle, restore the normal antitumor immune response of the body, so as to control and eliminate the tumor
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