A nanoadjuvant that dynamically coordinates innate immune stimuli activation enhances cancer immunotherapy and reduces immune cell exhaustion

Kinetics reshape antitumor immunity: Timing, duration, and combination are of importance for successful cancer immunotherapy

“…The design of t‐TLR7/8a was based on transient chemical shielding of the putative active site in TLR7/8a, specifically the C4 amine, which is known to interact with TLR7/8 through hydrogen bonding and recovery of activity via a chemical linker that can be cleaved in response to a specific signal within the endo/lysosomal microenvironment, such as gamma‐interferon‐inducible lysosomal thiol reductase (GILT) 6 (Figure 1A). Our study demonstrates that GILT, which is the only enzyme known to catalyze disulfide bond reduction in the endocytic pathway with an optimal pH of 4.5–5.5, facilitates the reduction of the disulfide bond of dormant TLR7/8a and the corresponding recovery of the active site of TLR7/8a in endo/lysosomes 5,7,8 . Notably, to the best of our knowledge, this study is the first that utilizes GILT as a trigger for the dynamic recovery of transiently dormant immunostimulants, providing a novel approach for dynamic immune modulation of APCs.…”

“…Adapted. 5 Copyright 2023 Springer Nature. 4.5-5.5, facilitates the reduction of the disulfide bond of dormant TLR7/8a and the corresponding recovery of the active site of TLR7/8a in endo/lysosomes.…”

Materials engineering strategies for cancer vaccine adjuvant development

“…In contrast, when the cells were first treated with R848 followed by polyI:C stimulation, the synergistic effect and inhibition of DC exhaustion were not observed. 69 Metal ions have been shown to have multiple important roles in fundamental life processes, including as enzyme cofactors and mediators of electron transport. 70 Recently, various immune processes have been reported to be manipulated by metal ions.…”

Single-Stranded RNA Origami-Based Epigenetic Immunomodulation

“…Both precise intracellular drug release and the synchronous effect of combinatorial drugs in a temporally and spatially ordered manner are crucial for ensuring the safety and effectiveness of immunotherapy. 35 After uptake by the cancer cell, the RNA nanostructure can be transported to the endolysosome, where highly active RNases, such as RNase T2, efficiently digest RNA. 36 As shown in Figure 4b and Figure S10, FUssRNA was completely degraded in 10% FBS after 1 h, whereas FUssROG remained stable in 10% FBS and only degraded after incubation with RNase T2 at a high concentration (10 μg/ mL).…”

“…We first evaluate the efficacy of drug release from FUssROG. Both precise intracellular drug release and the synchronous effect of combinatorial drugs in a temporally and spatially ordered manner are crucial for ensuring the safety and effectiveness of immunotherapy . After uptake by the cancer cell, the RNA nanostructure can be transported to the endolysosome, where highly active RNases, such as RNase T2, efficiently digest RNA .…”