Reveal myeloid cell-mediated targeting through nano-bio interface. Project Summary/Abstract Nanomedicine based on ultra-small nanoparticles (usNPs), such as dendrimers, gold NPs, quantum dots, and protein-based carriers (e.g., albumin), are at the forefront of clinical translation for targeting cancer and inflammatory disorders. Myeloid cells such as inflammatory monocytes (ФIMs) can traffic to the inflamed tissue and mediate the targeting of NPs to inflammation. However, the lack of mechanistic understanding of NP interaction with ФIMs and ФIM-mediated NP targeting to inflammation has significantly limited the rational design of tissue- or cell- specific delivery systems. A critical obstacle is that when NPs are injected into the blood, multiple serum proteins adsorb to the NP surface, forming a ‘NP proteome’. The NP proteome masks NP interaction with the cell surface and alters the NP cellular tropism. It is now recognized that it is the NP proteome rather than the NP physiochemical properties that dictate the NP cell tropism and more broadly their in vivo targeting behaviors. Toward this end, the overarching goal of my research program is to understand usNP–myeloid cell interactions and myeloid cell- mediated NP targeting to inflammation from the perspective of ‘NP proteome’ and to leverage myeloid cell recruitment to design inflammation-targeting nanotherapeutics. My research team has made significant strides in using animal models to characterize the trafficking of ФIMs to inflamed tissue and how ФIMs trafficking dynamics affect the deposition of usNPs. We also showed NP proteome is a critical mediator of usNP–ФIM interactions. Over the next five years, my research team will address key knowledge gaps that limit the rational design of inflammation- targeting nanotherapeutics. Specifically, for usNPs that carry drug payload on their surfaces, we will i) determine the fundamental mechanisms that govern usNP–ФIM interactions: we will establish a structure-property relation between the molecular properties of surface payload and NP proteome, and understand how NP proteomes are ‘read’ by ФIMs; ii) determine how myeloid cell recruitment mediates the targeting to inflammation for NPs carrying different payloads. The anticipated results will transform the current understanding of NP-myeloid cell interactions and have broad implications for nanotherapeutic targeting behaviors in vivo (e.g., tropism towards myeloid cells, biodistribution, targeting to inflammation), clearance, and toxicity (e.g., complement activation). iii) guided by this knowledge, we will develop a translatable nanotherapeutic that selectively delivers an immune modulator to target ФIMs and remove immunosuppression. As ever more nanotherapeutics are being tested in the clinics for various diseases and through diverse delivery routes (e.g., inhalation, intratumoral delivery), we envision this research program will set up the foundation for future studies to understand how NP proteom...