通过单细胞封装合成回路工程化细胞实现按需癌症免疫治疗

Despite the therapeutic potential of engineered immune cell therapy against metastases, it faces challenges including cytokine-driven systemic toxicity, off-target biodistribution, and host rejection.

Here, we develop red/far-red light-regulated individually encapsulated (RL/FRL-EnE) cells, integrating optogenetics with biomaterial encapsulation for precise immunomodulation. This system uses a phytochrome A-based photoswitch (ΔPhyA-PCB) that enables bidirectional control. RL (660 nanometers) triggers interferon-γ, interleukin-6, and anti-CD47 expression via ΔPhyA-PCB-far-red elongated hypocotyl 1 heterodimerization, while FRL (740 nanometers) rapidly reverses production, minimizing toxicity.

Single-cell nanoencapsulation prevents intercellular cross-talk and immune clearance, enabling strict light-dependent regulation and extended tumor residence. In vivo, RL/FRL-EnE cells remodeled the tumor microenvironment, reducing immunosuppressive myeloid cells (1. 3- to 1. 7-fold), while enhancing dendritic cell (1. 4-fold) and CD8 + T cell (2. 8-fold) infiltration. Collectively, this work establishes a paradigm for closed-loop cellular immunotherapy, where light-regulated living therapeutics achieve on-demand immune reprogramming.