Molecularly nanoengineered dendritic cells for tumor-specific antigen capture and sono-activatable cytokine-mediated immunotherapy.

Engineering artificial dendritic cells (DCs) holds great promise for cancer immunotherapy, but achieving spatiotemporally controlled multifunctionality within the immunosuppressive tumor microenvironment remains a challenge. Here, we report a chemically engineered, ultrasound (US)-activatable artificial DCs nanosystem (nDC-M) that mimics the DC-mediated T-cell immunity through a rationally designed molecular assembly. The nDC-M integrates three key functional modules including a semiconducting polymer nanoparticle and interleukin-2 (IL-2) crosslinked by hypoxia-cleavable fragment for on-demand cytokine release upon US trigger, a matured DC membrane cloak for tumor cell recognition and a surface-anchored maleimide (MAL) group for covalent antigen capture and presentation. Under US treatment, sonodynamic effect of semiconducting polymer ablates tumors and consumes oxygen to allow breakage of hypoxia-cleavable fragments, leading to IL-2 leakage. This nDC-M exhibits a comprehensive and conferred mimicking functions including tumor cell recognition, antigen presentation and sono-activatable cytokine secretion. In bilateral breast cancer and lung metastasis models, US-driven nDC-M therapy significantly suppresses tumor progression and metastasis. Moreover, combining nDC-M with checkpoint blockade achieves complete eradication of local and distant tumors and establishes long-term immunological memory against recurrence. This work presents a modular and stimuli-responsive artificial DC platform that integrates chemical synthesis, molecular nanoengineering, and function modulation, offering a versatile strategy for cancer immunotherapy.