Rational Design of Photosynthesis-Inspired Nanomedicines.

The sun is the most abundant source of energy on earth. Phototrophs have discovered clever strategies to harvest this light energy and convert it to chemical energy for biomass production. This is achieved in light-harvesting complexes, or antennas, that funnel the exciton energy into the reaction centers. Antennas contain an array of chlorophylls, linear tetrapyrroles, and carotenoid pigments spatially controlled by neighboring proteins. This fine-tuned regulation of protein-pigment arrangements is crucial for survival in the conditions of both excess and extreme light deficit. Photomedicine and photodiagnosis have long been utilizing naturally derived and synthetic monomer dyes for imaging, photodynamic and photothermal therapy; however, the precise regulation of damage inflicted by these therapies requires more complex architectures. In this Account, we discuss how two mechanisms found in photosynthetic systems, photoprotection and light harvesting, have inspired scientists to create nanomedicines for more effective and precise phototherapies. Researchers have been recapitulating natural photoprotection mechanisms by utilizing carotenoids and other quencher molecules toward the design of photodynamic molecular beacons (PDT beacons) for disease-specific photoactivation. We highlight the seminal studies describing peptide-linked porphyrin-carotenoid PDT beacons, which are locally activated by a disease-specific enzyme. Examples of more advanced constructs include tumor-specific mRNA-activatable and polyionic cell-penetrating PDT beacons. An alternative approach toward harnessing photosynthetic processes for biomedical applications includes the design of various nanostructures. This Account will primarily focus on organic lipid-based micro- and nanoparticles. The phenomenon of nonphotochemical quenching, or excess energy release in the form of heat, has been widely explored in the context of porphyrin-containing nanomedicines. These quenched nanostructures can be implemented toward photoacoustic imaging and photothermal therapy. Upon nanostructure disruption, as a result of tissue accumulation and subsequent cell uptake, activatable fluorescence imaging and photodynamic therapy can be achieved. Alternatively, processes found in nature for light harvesting under dim conditions, such as in the deep sea, can be harnessed to maximize light absorption within the tissue. Specifically, high-ordered dye aggregation that results in a bathochromic shift and increased absorption has been exploited for the collection of more light with longer wavelengths, characterized by maximum tissue penetration. Overall, the profound understanding of photosynthetic systems combined with rapid development of nanotechnology has yielded a unique field of nature-inspired photomedicine, which holds promise toward more precise and effective phototherapies.