Peptide nano ‘bead-grafting’ for SDT-facilitated immune checkpoints blocking

Combination therapies based on immune checkpoint blockade (ICB) are currently the mainstay of cancer treatment, in which the synergetic delivery of multiple drugs is the essential step. Although nanoparticle drugs (NPDs) show satisfactory anticancer effects, the promotion of active co-delivery of NPDs is premature, since the processes are usually difficult to predict and control. Targeting peptide self-assemblies have been widely used as carriers for small-molecular drugs, but remain elusive for NPDs. We describe here peptide-based nano ‘bead-grafting’ for the active delivery of quantum-dot NPDs through a co-assembly method. Based on a ‘de novo’ design, we used a ‘one-bead-one-compound (OBOC)’ combinatorial chemical screening method to select a peptide RT with high affinity for the immune checkpoint CD47, which could also form biocompatible nanofibers and efficiently trap Ag₂S quantum dots along the self-assembly path. This system can combine ICB therapy and sonodynamic therapy (SDT) to effectively inhibit tumor growth. Moreover, the tumor antigen produced by SDT can activate the adaptive immune system, which enhances the anti-tumor immune response of the ICB and shows efficient inhibition of both primary and distant tumors. This study provides a new strategy for the active control and delivery of NPDs and a new option for ICB therapy with immune checkpoints that are highly susceptible to systemic side effects.