ROS-responsive TLR7/8 nanoagonist and ultrasound modulate dendritic cells antigen presentation.

Immune checkpoint blockade (ICB) therapy represents a promising approach widely embraced for its sustained efficacy upon activation of the body's immune responses. Nonetheless, its effectiveness exhibits significant variability among patients, with a response rate below 30 %. A key limitation is the insufficient tumor infiltration and specific priming of CD8⁺ T cells. To address this, we develop ROS-responsive TLR7/8 nanoagonists {methoxy poly(ethylene glycol)- b -poly-[(N-2-hydroxyethyl)-aspartamide]- g -thioketal-R848}, designated as R848 NPs, wherein the C-4 amino of R848 is chemically blocked to enable selective release under endogenous tumor ROS conditions, thereby mitigating the severe systemic cytokine storms associated with R848. Additionally, ultrasound (US) is employed to induce immune cell death and facilitate intratumoral enrichment of R848 NPs. The proposed combination treatment, R848 NPs+US, effectively enhances antigen presentation by dendritic cells (DCs), facilitates intratumoral distribution of active R848, mitigates systemic inflammatory responses, promotes the release of damage-associated molecular patterns, and upregulates the expression of costimulatory molecules on DCs. Ultimately, R848 NPs+US plays a crucial role in bolstering CD8⁺ T cells immunity, synergizing with αPDL1 for CT26 tumor suppression (rate: 99.0 %, Q value: 1.68), eliciting memory immunity, and preventing tumor rechallenge. This work provides a novel strategy to potentiate the cancer immunity and a guidance for ICB therapy. [Display omitted] • ROS-responsive TLR7/8 nanoagonists (R848 NPs) for tumor treatment. • R848 NPs reduce the cytokine storm and systemic toxicity associated with R848. • R848 NPs and ultrasound boosts infiltration and specific priming of CD8⁺ T cells. • R848 NPs and ultrasound synergize with αPDL1, preventing tumor rechallenge. [ABSTRACT FROM AUTHOR]