CAREER: Sculpting light in biological tissue: an ultrasound-mediated traveling light source for spatiotemporally precise in vivo gene editing

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A fundamental challenge in biophotonics is the poor penetration of light deep inside the body due to scattering and absorption, thereby necessitating invasive procedures, such as optical fiber implantation and surgical tissue removal, to deliver light for deep-tissue imaging and light-activated therapies. To address this fundamental challenge, this CAREER project seeks to produce light on-demand at any depth or location inside the body via noninvasive ultrasound, thus realizing “light sculpting” in the body with user-defined patterns. The investigator’s group will use this method for spatially and temporally precise gene editing in deep tissue. The scientific outcomes of this CAREER project will enable the broadening participation of the Investigator and his group in a multitude of education activities. These education activities include K-12 outreach and teacher training, long-term mentorship to pre-college underrepresented minority (URM) students, and hands-on lab internship to students from underserved high schools and historically Black colleges and universities (HBCUs). The overarching career goal of the investigator is to bridge the gap in knowledge and eliminate the barrier between the physical and life sciences. Towards this goal, this CAREER project aims to develop a circulation deliverable and rechargeable light source under an engineered ultrasound field, thereby leading to on demand “light sculpting” in three-dimensional biological tissue and thus address the fundamental challenge of biophotonics of delivering light to a depth of more than 100 microns. The project’s main hypothesis is that traveling mechanoluminescent nanoparticles (MLNPs) in blood circulation can act as an energy relay that transports demand generation of localized light emission by circulating MLNPs (cyan circles) and tissue-penetrant FUS (focused ultrasound) for gene editing. The research plan is organized under three objectives: the FIRST objective is to develop a palette of rare-earth doped melilite phosphor MLNPs with tunable emission wavelengths in response to different ultrasound frequencies. With mechanistic understanding of the relationship between ultrasound pressure, emission wavelength and trap depth of MLNPs, the SECOND objective is to obtain user-defined spatiotemporal pattern of light emission in any biological tissue based on the simulated ultrasound pressure field, local hemodynamics, and the photophysical properties of blood-circulating MLNPs. The THIRD objective is to perform in vivo "light sculpting" with ultrasound for spatiotemporally precise gene editing in live mice, using photo switchable Cas9 and a bioluminescent reporter to assess success. If successful, this technology can be widely extended to any application requiring a light source deep in the body, including in vivo fluorescence microscopy, deep-brain optogenetics, and photodynamic therapies to treat cancer and viral infections.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.