Modular Assembly of Photoactive Lipid Nanoparticles on Red Blood Cells toward Enhanced Phototherapy Efficacy

Photodynamic therapy has been developed as a promising treatment for malignant tumors, which inspires research into photosensitizers. However, the therapeutic efficacy of individual photosensitizers is often hampered by the physiological environment. The assembly of biological materials with synthetic molecules offers a strategy to enhance functionality while improving tolerance to varying physiological conditions. Herein, we present a biohybrid system for enhanced phototherapy efficacy through a simple two-step assembly process. Photoactive lipid nanoparticles were assembled based on synthesized conjugated molecules and lipophilic prodrugs, which were then modularly assembled with red blood cells (RBCs). Driven by hydrophobic and electrostatic interactions, hydrophobic conjugated molecules were efficiently incorporated into the RBCs, while lipophilic prodrugs were simultaneously inserted into the cell membranes. The engineered RBCs harnessed the natural oxygen transport capability, enabling the internal conjugated molecules to effectively produce reactive oxygen species (ROSs) even under oxygen-poor conditions. Meanwhile, the use of ROS-cleavable linkers in prodrugs enhanced drug release for chemotherapy, which is a perfect complement to photodynamic therapy. In vitro and in vivo experiments proved the improved phototherapy efficacy of the biohybrid system. Furthermore, the changes in aggregation directed Förster resonance energy transfer between conjugated molecules and fluorescent drugs provided a mechanism to track drug release from engineered RBCs. Therefore, the modular assembly of biohybrid systems can offer multiple functionalities required for phototherapy, on-demand drug release, and imaging.