Precisely engineering a carrier-free hybrid nanoassembly for multimodal DNA damage-augmented photodynamic therapy

Abstract Photodynamic therapy (PDT) has been extensively explored for cancer treatment. There is growing evidence showing that oxidative DNA damage caused by the vast accumulation of reactive oxygen species (ROS) in tumor cells plays a dominant role in accelerating cell apoptosis. Nevertheless, the repair pathways of aberrant DNA in tumor cells help reduce and reverse such damage. Thus, a precise combination of photodynamic photosensitizers and DNA repair inhibitors is expected to significantly augment the PDT efficacy. But it remains challenging to achieve accurate co-delivery of two drugs into the target sites. Herein, an ingenious dual-drug assembly modality is developed to precisely engineer a novel co-delivery nanomedicine. For proof-of-concept, a carrier-free hybrid nanoassembly of etoposide (VP-16) and pyropheophorbide a (PPa) is elaborately fabricated for multimodal DNA damage-mediated synergistic cancer therapy. Generally, this study exhibits a facile and practical dual-drug co-assembly engineering strategy, constructs an efficient and versatile co-delivery nanoplatform, and enables significant combination anticancer efficacy in vitro and in vivo. Such a dual-drug hybrid nanoassembly has the potential to be utilized as a promising nanomedicine for clinical multimodal cancer therapy.