Abstract: We will design a multistage, combination therapy polymersomes that will differentially respond to extra- and intracellular pH existing in pancreatic ductal adenocarcinoma (PDAC) microenvironment. These carriers will be assembled from amino-functionalized block copolymers with a distinct self-assembly behavior exclusively governed by their ionization status. Using tumor homing and penetrating peptides such as iRGD, the nanoparticles will be rendered to overcome desmoplasia induced ‘kinetic barrier’ to payload delivery in solid tumors. The innovation of the project lies in the fact that, the direct contribution of the altered acid-base transport machinery of pancreatic ductal cells, which is one of the hallmarks of PDAC progression, and the evolutionary conserved intracellular lysosomal acidity will be used as mechanistic promoters of drug release to simultaneously engage multiple micro-environmental and intracellular targets. The research objectives of this proposal are to understand how pH-responsive block copolymer assembly influences in vitro and in vivo efficiency of a combination chemotherapy that can inhibit the crosstalk between malignant cells and their stromal components. The creation of orthogonal pHresponsive systems with controlled assembly/disassembly property will also provide a clear understanding of the structure-activity relationship of amino-functionalized polyester block copolymers for attaining systemic stability and deep tissue penetration so that they can be applied in therapeutic setting. Finally, the project will enable the PI’s translation and graduation as an independent investigator in the area of pancreatic cancer research.