Curated Optogenetic Publication Database

Abstract: In the immunosuppressive tumor microenvironment (TME), tumor-associated macrophages (TAMs) predominantly exhibit an immunosuppressive M2 phenotype, which facilitates tumor proliferation and metastasis. Although current strategies aimed at reprogramming TAMs hold promise, their sustainability and effectiveness are limited due to repeated injections. Herein, a bacterial therapy platform containing two engineered strains was developed. One strain was engineered to produce and secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) to promote M2-like TAMs repolarization to M1-like TAMs, while the other strain was designed to secrete small interfering RNA (siRNA) targeting signal regulatory protein α (SIRPα). The two strains can continuously and efficiently produce bioactive therapeutic agents in situ, exerting a sustained and synergistic therapeutic effect in TAMs to inhibit tumor growth. To enhance treatment efficacy, optogenetic strategy was implemented to effectively control the production of GM-CSF, and outer membrane vesicles (OMVs) produced by engineered bacteria were utilized to protect the siRNA from degradation in the external environment. The experimental results indicated that the bacterial therapy platform could continuously produce and release bioactive GM-CSF and SIRPα siRNA, exhibiting significant therapeutic activity. In vivo experiments further demonstrated that this platform showed more sustained and stable therapeutic effects compared to conventional drug therapies. Additionally, the combination of these two engineered strains yielded the highest ratio of M1/M2 TAMs (0.80) and the lowest ratio of F4/80+SIRPα+TAMs (3.46 %) than single strain therapy. Our study expanded the potential of engineered bacteria as pharmaceutical factories for in vivo therapeutic applications.

Abstract: Engineered bacteria-based cancer therapy has increasingly been considered to be a promising therapeutic strategy due to the development of synthetic biology. Wherein, engineering bacteria-mediated photodynamic therapy (PDT)-immunotherapy shows greater advantages and potential in treatment efficiency than monotherapy. However, the unsustainable regeneration of photosensitizers (PSs) and weak immune responses limit the therapeutic efficiency. Herein, we developed an engineered bacteria-based delivery system for sequential delivery of PSs and checkpoint inhibitors in cancer PDT-immunotherapy. The biosynthetic pathway of 5-aminolevulinic acid (5-ALA) was introduced into Escherichia coli, yielding a supernatant concentration of 172.19 mg/L after 10 h of growth. And another strain was endowed with the light-controllable releasement of anti-programmed cell death-ligand 1 nanobodies (anti-PD-L1). This system exhibited a collaborative effect, where PDT initiated tumor cell death and the released tumor cell fragments stimulated immunity, followed by the elimination of residual tumor cells. The tumor inhibition rate reached 74.97%, and the portion of activated T cells and inflammatory cytokines were reinforced. The results demonstrated that the engineered bacteria-based collaborative system could sequentially deliver therapeutic substance and checkpoint inhibitors, and achieve good therapeutic therapy. This paper will provide a new perspective for the cancer PDT-immunotherapy.

Abstract: Microbes regulate brain function through the gut-brain axis, deriving the technology to modulate the gut-brain axis in situ by engineered probiotics. Optogenetics offers precise and flexible strategies for controlling the functions of probiotics in situ. However, the poor penetration of most frequently used short wavelength light has limited the application of optogenetic probiotics in the gut. Herein, a red-light optogenetic gut probiotic was applied for drug production and delivery and regulation of the host behaviors. Firstly, a Red-light Optogenetic E. coli Nissle 1917 strain (ROEN) that could respond to red light and release drug product by light-controlled lysis was constructed. The remaining optical power of red light after 3 cm tissue was still able to initiate gene expression of ROEN and produce about approximately 3-fold induction efficiency. To give full play to the in vivo potential of ROEN, its responsive ability of the penetrated red light was tested, and its encapsulation was realized by PH-sensitive alginate microcapsules for further oral administration. The function of ROEN for gut-brain regulation was realized by releasing Exendin-4 fused with anti-neonatal Fc receptor affibody. Neuroprotection and behavioral regulation effects were evaluated in the Parkinson's disease mouse model, after orally administration of ROEN delivering Exendin-4 under optogenetic control in the murine gut. The red-light optogenetic probiotic might be a perspective platform for in situ drug delivery and gut-brain axis regulation.