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 α_vβ₃ 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.

一个名为LightOn基因表达系统的可光开关转基因系统可以在蓝光下以高开/关比调节基因表达，并且具有时空可控的基因表达潜力。我们开发了一种纳米颗粒药物递送系统（NDDS），以实现对肿瘤微环境的响应，并将白喉毒素A（DTA）片段编码的质粒靶向递送至肿瘤部位。通过暴露于蓝光诱导DTA的表达。聚乙烯亚胺和维生素E琥珀酸酯通过二硫键连接，和聚乙二醇化透明质酸与RGD肽修饰，在肿瘤组织中积累的组成和纳米颗粒积极内化到4T1细胞通过双重靶向CD44和α _v β ₃受体。LightOn基因表达系统能够通过调节蓝光暴露的强度或持续时间来控制靶蛋白的表达。体外研究表明，光诱导的DTA表达降低了4T1细胞的活力并诱导了细胞凋亡。此外，LightOn基因表达系统能够在小鼠4T1肿瘤异种移植模型中时空控制DTA的表达，从而产生出色的抗肿瘤作用，减少的肿瘤血管生成和无全身毒性。LightOn基因表达系统和NDDS的组合可能是治疗乳腺癌的有效策略。