Near‐Infrared Nano‐Optogenetic Activation of Cancer Immunotherapy via Engineered Bacteria

Abstract

Certain obligate and facultative anaerobic microbes preferentially grow within this region, [2,3] which makes them ideal platforms for delivering antitumor therapeutics. [4,5] Different from conventional nano-drug delivery systems, bacteria-based drug carriers can be designed to generate and release drugs, which avoids the need for cumbersome post-purification or delivery protection. [6] However, bacteria sometimes can grow outside their natural niches, leading to offtarget therapeutics release that may incur severe toxicities toward normal tissues. [7,8] Therefore, it is crucial to "tune" the bacteria for precise and on-demand release of the therapeutics at the tumor site so as to minimize the side effects as well as promote antitumor therapeutic efficacy.Spatial and temporal activation of inducible or repressible gene expression systems facilitate precise gene expression as required. Ideally, programming bacteria with the capability to rapidly and precisely switch between "ON" and "OFF" states at will, would sense and respond to the physiological or pathological conditions upon utilization of certain stimuli. [9] Typically, exogenous chemical inducers, such as antibiotics, were used to achieve artificial control of gene expression in live cells. [10] However, it is very difficult to remove the residual chemical inducers, which limited the precise control of gene expression at desired levels. Light, as an external inducer, possesses high spatiotemporal control ability, non-invasiveness, and minimal cytotoxicity. Therefore, light-regulated modules have attracted wide attention for controlling molecular or cellular behavior. Among them, optogenetics combines optics and genetics in technology to rapidly activate/deactivate photo-sensitive proteins, which shows great potential in the modulation of neural activities, gene transcription, and the regulation of cellular processes within organisms. [11] Most of these applied optogenetics are blue light (BL)-based control systems, including CRY2/CIB, [12] VVD, [13] EL222, [14,15] and magnet systems. [16] However, a major hurdle in these optogenetics systems stems from poor BL penetration to turbid human tissues and potential phototoxicity. It was also noted that some red/far-red light-responsive optogenetic devices, phyB/PIF1/SPA1, [17] BphP1/PpsR2 [18] and BphS, [19] have been developed to control transgene expression. However, the in Certain anaerobic microbes with the capability to colonize the tumor microenvironment tend to express the heterologous gene in a sustainable manner, which will inevitably compromise the therapeutic efficacy and induce off-tumor toxicity in vivo. To improve the therapeutic precision and controllability of bacteriabased therapeutics, Escherichia coli Nissle 1917 (EcN), engineered to sense blue light and release the encoded flagellin B (flaB), is conjugated with lanthanide upconversion nanoparticles (UCNPs) for near-infrared (NIR) nano-optogenetic cancer immunotherapy. Upon 808 nm photoirradiation, UCNPs emit at the blue region to photoactivat...

Putting Hybrid Nanomaterials to Work for Biomedical Applications

“…For example, certain species of Escherichia coli (E. coli) exhibit the capability to sense blue light and release the encoded flagellin B. Leveraging these properties, a bacteria-based biohybrid was constructed with E. coli and lanthanide UCNPs for optogenetic cancer immunotherapy. [64] In addition, an "immune guide" based on magnetite nanoparticles was developed to recruit and activate macrophages for enhanced immunotherapies. [62] Alternatively, the nanostructures can be enclosed by the membranes derived from cells to form a biohybrid system.…”

“…Emission of light at shorter wavelengths than incident lights without blinking Photodynamic therapy and optical tracking [42] Gd-doped Au nanoparticles Magnetic activity and optical responsiveness Contrast agents for multi-modal imaging and imageguided therapy [43] Gd-doped CuS nanoparticles Magnetic activity and optical absorption Contrast agents for multi-modal imaging; localized hyperthermia; and image-guided therapy [44] Cu nanoparticles Radioactivity for 64 Cu Probe for positron emission tomography (PET) [45,46] Graphene and graphene oxide (GO) Flexibility and structural reinforcement; catalytic activity; and conductivity Drug delivery and tissue repair or regeneration [47] Iron manganese silicate nanoparticles (IMSN)…”

Hybrid Bacteria System with Nanomaterials for Tumor Therapy

“…This work provided an NIR‐photoactivable hybrid bacteria systems based on optogenetics for tumor immunotherapy. [ 101 ] Other than light‐induced control elements, temperature‐based transcriptional regulators can be an alternative strategy for spatiotemporal control. Among them, some emerging studies have demonstrated that focused ultrasound can generate thermal bioswitches to control the expression of bacterial gene by constructing a temperature‐actuated therapeutic circuit.…”

Genetically engineered bacteria: a new frontier in targeted drug delivery

“…Public opinion about GMOs is often divided, with concerns about their safety, ethics, and potential environmental impact contributing to skepticism and resistance. [167][168][169][170] In light of this, fostering public trust and acceptance is critical for the successful implementation of GEB applications in healthcare. This can be achieved through transparent communication about the benefits and risks of GEB, as well as the measures taken to ensure their safety.…”