Toll-like receptor (TLR) agonists are potent immune-stimulators that hold great potential in vaccine adjuvants as well as cancer immunotherapy. Compared with traditional adjuvants such as alum and emulsion adjuvants, TLR agonists hold the advantages of high immune-stimulating efficacy and the clear mechanism. However, TLR agonists in free form are prone to be eliminated quickly by the circulatory system and cause systemic inflammation side effects. It remains a challenge to achieve precise release of TLR7/8 agonist in the native form at receptor site in the endosomal compartments while keeping stable encapsulation and inactive in non-target environment.<br/>Herein, we designed a TLR7/8 agonist conjugated nanovaccine (TNV) to activate the TLR7/8 signaling for robust cancer immunotherapy. TNV was engineered by our developed ultra-pH-sensitive (UPS) nanomaterials, which have been demonstrated to possess sharp pH responsiveness (pH<sub>10-90%</sub> &lt; 0.25) and precise organelle targeting capability. IMDQ, the selected TLR7/8 agonist, was covalently conjugated to the hydrophobic block of the pH-responsive block copolymer through an enzyme-responsive linkage, Gly-Phe-Leu-Gly (GFLG), which could self-assemble into core-shell nanoparticles. TNV responds intelligently to the acidic environment and cathepsin B in the endosome, precisely releases TLR7/8 agonist to activate its receptor signaling at endosomal membrane, stimulates DCs maturation and provokes specific cellular immunity. In vivo experiments demonstrate outstanding prophylactic and therapeutic efficacy of TNV in mouse melanoma and colon cancer. The endosome-targeted responsive nanoparticle strategy provides a potential delivery toolbox of adjuvants to advance the development of tumor nanovaccines.

pH-/enzyme-responsive nanoparticles selectively targets endosomal Toll-like receptors to potentiate robust cancer vaccination

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