Modular Assembly\nof Photoactive Lipid Nanoparticles\non Red Blood Cells toward Enhanced Phototherapy Efficacy

Photodynamic therapy has been developed as a promising\ntreatment\nfor malignant tumors, which inspires research into photosensitizers.\nHowever, the therapeutic efficacy of individual photosensitizers is\noften hampered by the physiological environment. The assembly of biological\nmaterials with synthetic molecules offers a strategy to enhance functionality\nwhile improving tolerance to varying physiological conditions. Herein,\nwe present a biohybrid system for enhanced phototherapy efficacy through\na simple two-step assembly process. Photoactive lipid nanoparticles\nwere assembled based on synthesized conjugated molecules and lipophilic\nprodrugs, which were then modularly assembled with red blood cells\n(RBCs). Driven by hydrophobic and electrostatic interactions, hydrophobic\nconjugated molecules were efficiently incorporated into the RBCs,\nwhile lipophilic prodrugs were simultaneously inserted into the cell\nmembranes. The engineered RBCs harnessed the natural oxygen transport\ncapability, enabling the internal conjugated molecules to effectively\nproduce reactive oxygen species (ROSs) even under oxygen-poor conditions.\nMeanwhile, the use of ROS-cleavable linkers in prodrugs enhanced drug\nrelease for chemotherapy, which is a perfect complement to photodynamic\ntherapy. In vitro and in vivo experiments proved the improved phototherapy\nefficacy of the biohybrid system. Furthermore, the changes in aggregation\ndirected Förster resonance energy transfer between conjugated\nmolecules and fluorescent drugs provided a mechanism to track drug\nrelease from engineered RBCs. Therefore, the modular assembly of biohybrid\nsystems can offer multiple functionalities required for phototherapy,\non-demand drug release, and imaging.