NOX2 Enzyme Mimicking Nano‐Networks Regulate Tumor‐Associated Macrophages to Initiate Both Innate and Adaptive Immune Effects

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 (“O2 to O2•− to H2O2/•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.