PPS-TLR7/8 agonist nanoparticles equip robust anticancer immunity by selectively prolonged activation of dendritic...

Checkpoint inhibitor therapies do not benefit all patients, and adjuvants play a critical role in boosting immune responses for effective cancer immunotherapy. However, their systemic toxicity and suboptimal activation kinetics pose significant challenges. Here, this study presented a linker-based strategy to modulate the activation kinetics of Toll-like receptor 7/8 (TLR7/8) agonists delivered via poly (propylene sulfide) nanoparticles (PPS NPs). By covalently binding small molecule TLR7/8 agonists to PPS NPs with different linkers, enhanced therapeutic efficacy is achieved while abrogating systemic toxicity. These results showed that an alkyl linker selectively prolong the activation of DCs. It avoided the extensive activation of other APCs, favoring the limitation of immune-related toxicities. This strategy exhibited significant anti-tumor activity in alkyl linked nano-TLR7/8 agonists treatment alone, and cytokine and immune cell profiling provided evidence of prolonged immune cell activation in the tumor microenvironment, with evidence of an increase in the frequency of tumor antigen-specific CD8⁺ T cells. This linker-based approach offers a promising strategy to optimize the delivery of nano-TLR7/8 agonists for cancer immunotherapy, potentially advancing the field toward improved clinical outcomes.