Curated Optogenetic Publication Database

Abstract: Sepsis is a comprehensive ailment of systemic inflammatory response syndrome arising from infection. Activation of CASPASE-1 plays a central role in initiating the inflammatory cascade during sepsis. Herein, we construct optogenetically engineered extracellular vesicles (EVs) that achieve the specific degradation of CASPASE-1 and inhibit sepsis-associated inflammation. Specifically, blue light (460 nm)-induced CRY2/CIBN heterodimerization was applied during the EVs production stage to selectively load GCE-CTM fusion proteins into EVs by EXPLORs technology, yielding EVsGCE-CTM loading efficiency compared to conventional methods. Upon systemic delivery, EVsGCE-C TM preferentially accumulated in macrophages, where the GCE domain selectively bound activated CASPASE-1. The CTM motif then facilitated its lysosomal degradation by chaperone-mediated autophagy, resulting in potent inhibition of CASPASE-1 activity. In a murine model of sepsis, treatment with EVsGCE-CTM effectively attenuated systemic inflammation, reduced multi-organ damage, and significantly improved survival outcomes. This approach enables highly efficient, ubiquitin-independent degradation of intracellular target proteins through macrophage-directed EVs delivery, offering a potential therapeutic approach to address sepsis and other inflammation-related diseases.

Abstract: Immunotherapy emerged as a paradigm shift in cancer treatments, which can effectively inhibit cancer progression by activating the immune system. Remarkable clinical outcomes have been achieved through recent advances in cancer immunotherapy, including checkpoint blockades, adoptive cellular therapy, cancer vaccine, and tumor microenvironment modulation. However, extending the application of immunotherapy in cancer patients has been limited by the low response rate and side effects such as autoimmune toxicities. With great progress being made in nanotechnology, nanomedicine has been exploited to overcome biological barriers for drug delivery. Given the spatiotemporal control, light-responsive nanomedicine is of great interest in designing precise modality for cancer immunotherapy. Herein, we summarized current research utilizing light-responsive nanoplatforms to enhance checkpoint blockade immunotherapy, facilitate targeted delivery of cancer vaccines, activate immune cell functions, and modulate tumor microenvironment. The clinical translation potential of those designs is highlighted and challenges for the next breakthrough in cancer immunotherapy are discussed.

Abstract: A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light, and have great potential for spatiotemporally controllable gene expression. We developed a nanoparticle drug delivery system (NDDS) to achieve tumor microenvironment-responsive and targeted delivery of diphtheria toxin A (DTA) fragment-encoded plasmids to tumor sites. The expression of DTA was induced by exposure to blue light. Nanoparticles composed of polyethylenimine and vitamin E succinate linked by a disulfide bond, and PEGylated hyaluronic acid modified with RGD peptide, accumulated in tumor tissues and were actively internalized into 4T1 cells via dual targeting to CD44 and αvβ3 receptors. The LightOn gene expression system was able to control target protein expression through regulation of the intensity or duration of blue light exposure. In vitro studies showed that light-induced DTA expression reduced 4T1 cell viability and induced apoptosis. Furthermore, the LightOn gene expression system enabled spatiotemporal control of the expression of DTA in a mouse 4T1 tumor xenograft model, which resulted in excellent antitumor effects, reduced tumor angiogenesis, and no systemic toxicity. The combination of the LightOn gene expression system and NDDS may be an effective strategy for treatment of breast cancer.