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...
