CONSPECTUS: Nanomedicine development aims to enhance the efficacy, accuracy, safety, and/or compliance of diagnosis and treatment of diseases by leveraging the unique properties of engineered nanomaterials. To this end, a multitude of organic and inorganic nanoparticles have been designed to facilitate drug delivery, sensing, and imaging, some of which are currently in clinical trials or have been approved by the Food and Drug Administration (FDA). In the process, the increasing knowledge in understanding how natural particulates, including cells, pathogens, and organelles, interact with body and cellular systems has spurred efforts to mimic their morphology and functions for developing new generations of nanomedicine formulations. In addition, the advances in bioengineering tools, bioconjugation chemistries, and bio-nanotechnologies have further enabled researchers to exploit these natural particulates for theranostic purposes. In this Account, we will discuss the recent progress in our lab on engineering bioinspired and biomimetic synthetic and cellular systems toward rational design of nanomedicine platforms for treating diabetes and cancer. Inspired by the structure and response mechanism of pancreatic beta-cells, we synthesized a series of insulin granule-like vesicles that can respond to high blood or intestinal glucose levels for aiding in transdermal or oral insulin delivery, respectively. Then, to more closely mimic the multicompartmental architecture of beta-cells, we further developed synthetic artificial cells with vesicle-in-vesicle superstructures which can sense blood glucose levels and dynamically release insulin via a membrane fusion process. Meanwhile, clues drawn from the traits of anaerobic bacteria that selectively invade and proliferate in solid tumors inspired the synthesis of a light-tuned hypoxia-responsive nanovesicle for implementing synergistic cancer therapy. In parallel, we also studied how autologous particulates could be recruited for developing advanced drug delivery systems. Through combination of genetic engineering and top-down cell engineering technologies, biomimetic nanomedicines derived from cytoplasmic membrane with programmed death 1 (PD-1) receptors expressed on surfaces were generated and employed for cancer immunotherapy. Based on our earlier study where aPD-L1 (antibodies against PD ligand 1)-conjugated platelets could release aPD-L1-bearing particles in situ and inhibit postsurgical tumor recurrence, we further genetically engineered megakaryocytes, the precursor cells of platelets, to express PD-1 receptors. In this way, platelets born with checkpoint blocking activity could be produced directly in vitro, avoiding post chemical modification processes while exerting similar therapeutic impact. As a further extension, by virtue of the bone marrow homing ability of hematopoietic stem cells (HSCs), we recently conceived a cell-combination strategy by conjugating HSCs with platelets decorated with antibodies against PD1 (aPD-1) to suppress the growth and recurrence of leukemia. While we are still on the way of digging deep to understand and optimize bioinspired and biomimetic drug carriers, we expect that the strategies summarized in this Account would contribute to the development of advanced nanomedicines.
