Upconversion Nanoparticle-Anchored\nMetal–Organic\nFramework Nanostructures for Remote-Controlled Cancer Optogenetic\nTherapy

Optogenetics, a revolutionary technique utilizing light-sensitive\nproteins to control cellular functions with high spatiotemporal precision,\npresents a promising avenue for disease treatment; however, its application\nin cancer therapy remains constrained by limited research. Herein,\nwe introduce a pioneering strategy for remote-controlled optogenetic\ncancer therapy, synergistically merging optogenetics with ion therapy,\nwhich incorporates ion self-supply, in situ ion channel construction,\nand near-infrared (NIR) light-activated ion therapy, facilitating\nremote and noninvasive manipulation of cellular activities in deep\ntissues and living animals. We report the facile synthesis of water-dispersible\nupconversion nanoparticle (UCNP)–metal–organic framework\n(MOF) nanohybrids capable of effectively delivering plasmid DNA to\ncancer cells, thereby enabling the in situ expression of photoactivatable\ncation channels. The pH-responsive MOF components serve as a reservoir\nfor metal cations, which are released in the acidic microenvironment\nof tumors, while the UCNP components function as remote-controlled\ntransducers, converting near-infrared (NIR) light into visible light\nto activate the cation channels and allowing the cancer influx of\nreleased metal cations for ion therapy. The proposed remote-controlled\ncancer optogenetic therapy demonstrates its effectiveness across multiple\ntumor models, including subcutaneous colon tumors, subcutaneous breast\ntumors, and orthotopic breast tumors. This study represents a significant\nstep toward the realization of optogenetics in clinics, with substantial\npotential for advancing cancer therapy.