Cyanobacteria-intelligent biohybrid system enables light-guided tumor-associated macrophage-specific siRNA delivery

<h2>Summary</h2> Tumor-associated macrophages (TAMs) play a critical role in tumor immune evasion and metastasis, but efficiently delivering nucleic acids to reprogram TAMs <i>in vivo</i> remains a challenge. Here, we develop a biohybrid system (CTPA/siCSF1R) specifically targeting TAMs, aiming to conduct spatiotemporal manipulation of precise small interfering RNA (siRNA) delivery. The inherent self-driven and phototactic abilities of cyanobacterium <i>Synechocystis</i> sp. PCC6803 (cyan) facilitate the targeted accumulation of CTPA/siCSF1R within TAMs, guided by a 660 nm laser. The light-guided reactive oxygen species production by cyan and the protonation of the triblock polyamino acid gene vector contribute to the remarkable "lysosome escape" capability of siRNA, thereby promoting TAM repolarization to the M1 phenotype. Furthermore, photosynthetic oxygen produced from cyan in conjunction with TAM-specific genetic reprogramming induces an effective immune response to inhibit tumor growth. This light-guided biohybrid system represents a promising strategy for the development of efficient and safe nucleic acid delivery vectors and tumor photoimmunotherapy.