Recently, a research team led by Prof. CAI Lintao from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences, developed an innovative intelligent light-guided biohybrid system, the CTPA/siCSF1R, to target tumor-associated macrophages (TAMs), enabling precise spatiotemporal (small interfering RNA) siRNA delivery. This system enhances the tumor microenvironment and supports precise photoimmunotherapy.

This study was published in Cell Reports Physical Science on Nov. 25.

TAMs are crucial immune cells in the tumor microenvironment and key targets for tumor immunotherapy, where gene therapy is a significant approach. However, existing gene carriers face challenges, such as poor targeting, limited lysosomal escape, and the negative effects of a hypoxic immunosuppressive microenvironment, which limit their clinical efficacy.

In this study, researchers employed a living biological carrier, Cyanobacterium Synechocystis sp. PCC6803 ("cyan"), which exhibits self-driven tumor targeting and phototactic capabilities. These characteristics make it an excellent vehicle for precise drug delivery under controllable external forces. Consequently, cyan's phototactic behavior, along with its ability to produce oxygen through photosynthesis, holds promising potential for delivering nucleic acid drugs to solid tumors.

The CTPA/siCSF1R system consists of a triblock polyamino acid (TPA) gene vector encapsulating siRNA, which is conjugated to the surface of photosynthetic cyanobacteria.

"Our system utilizes the inherent self-driven and phototactic abilities of cyanobacteria to achieve precise targeting of TAMs within the tumor microenvironment," said Prof. CAI.

The light-guided production of reactive oxygen species by cyanobacteria and the protonation of TPAs disrupted the lysosomal membrane, facilitating the release of siRNA into the cytoplasm of TAMs. Meanwhile, oxygen produced by cyanobacteria through photosynthesis enhanced the tumor microenvironment, promoting the efficacy of siRNA delivery and the reprogramming of TAMs.

Experimental results showed that CTPA/siCSF1R effectively reprograms TAMs to the M1 phenotype, promotes the production of pro-inflammatory cytokines, and induces a strong immune response that inhibits tumor growth. Furthermore, the system exhibits excellent biosafety and does not cause significant toxicity to the organism.

The proposed system offers a promising approach for developing both efficient and safe nucleic acid delivery vectors and for advancing tumor photoimmunotherapy.

Schematic illustration of cyanobacteria-intelligent hybrid systems realizing light-guided TAM-specific siRNA delivery for antitumor photoimmunotherapy. (Image by SIAT)

Media Contact: LU Qun

Email: qun.lu@siat.ac.cn

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