Project Summary Despite being hailed as the “magic bullet” that would selectively target and cure cancer, only a handful of nanoparticles have been successfully translated to the clinic, and their full potential remains yet to be realized. In fact, nanoparticle accumulation in tumors continues to be dismally low, with less than 1% of the injected dose reaching its target. This is largely attributed to the complexity and heterogeneity of both the biological environment and nanoparticle constructs, making it impossible to deconvolute individual factors contributing to nanoparticle targeting and accumulation in tumors. Therefore, there is a critical need to better understand and define the attributes that define successful nanocarriers. This is particularly urgent in lethal cancers that stand to benefit tremendously from new and targeted therapies, like ovarian cancer, which has a 25% 5-year survival rate and 70% recurrence rate following chemotherapy, often leading to treatment resistant disease. To develop effective drug delivery strategies, it is critically important to understand the characteristics of tumors, nanoparticles, and their interactions, such as by identifying the genetic features associated with high nanoparticle uptake and accumulation. To accomplish this, the work proposed herein features a chemical barcoding approach to enable pooled high throughput analysis of nanoparticles in a pre-clinical context, enabling the identification and correlation of genetic features responsible for successful nanoparticle targeting through a multi-omics approach. Successful development of this barcoding platform will entail 1) rapid integrated in vitro screening of pooled NP formulations, 2) in vivo single system evaluation of nanoparticle accumulation at the tissue and cellular level, and 3) use of pooled barcoded nanoparticles to correlate particle trafficking in patient derived models of ovarian cancer. This strategy will provide a holistic evaluation of nanoparticle structure-function relationships with tumor accumulation and enable the identification of genetic components implicated with meaningful nanoparticle interactions, allowing us to leverage these signatures to develop more effective targeted nanoparticles to specific tumor cell populations. The proposed work will take place at MIT’s Koch Institute for Integrative Cancer Research, a premier institution for cancer research with state-of-the-art facilities, under the mentorship of Prof. Paula Hammond, a renowned chemical engineer and polymer chemist with expertise in the self-assembly of materials and drug delivery. An advisory team has carefully been assembled, consisting of Profs. Stuart Schreiber and Angela Koehler for chemical biology and multi-omics analysis guidance, Prof. Joan Brugge for her cancer biology expertise, and Prof. Nathalie Agar for input on mass spectrometry-based analysis. Combined, this research proposal and mentorship team will lay the scientific groundwork and provi...