Close and Enhance the Cancer-Immunity Cycle by Engineered Dual-Targeted Nano-Adaptors.

Abstract

The cancer-immunity cycle (CIC) provides a conceptual framework for eliciting effective anti-tumor immune responses by targeting key events in systemic immunity. However, the successful completion of the CIC often requires the coordinated action of multiple therapeutic modalities, necessitating their integration into a unified system to overcome the limitations of conventional combination therapies. Here, we present a multimodal and programmable platform that integrates diverse therapeutic biomolecules into single agents, enabling the construction of versatile nanomedicines and bispecific antibodies through dual-targeted nano-adaptor (TNA) nanotechnology to potentiate the CIC. Specifically, TNA nanomedicines target five critical steps within the CIC, including antigen release, dendritic cell (DC) maturation, T-cell activation, mitigation of T-cell exhaustion, and tumor cell killing. Meanwhile, TNA bispecific antibodies enhance DC-T cell interactions to strengthen adaptive immunity and reinforce NK-tumor cell interactions to promote cytotoxicity. We demonstrate that TNAs elicit robust anti-tumor immunity, eradicating established tumors and suppressing metastatic dissemination. Owing to their modular and programmable architecture, TNAs hold broad potential for applications in immunotherapy and beyond.