Recent advances in drug delivery and targeting for the treatment of pancreatic cancer.

Despite significant treatment efforts, pancreatic ductal adenocarcinoma (PDAC), the deadliest solid tumor, is still incurable in the preclinical stages due to multifacet stroma, dense desmoplasia, and immune regression. Additionally, tumor heterogeneity and metabolic changes are linked to low grade clinical translational outcomes, which has prompted the investigation of the mechanisms underlying chemoresistance and the creation of effective treatment approaches by selectively targeting genetic pathways. Since targeting upstream molecules in first-line oncogenic signaling pathways typically has little clinical impact, downstream signaling pathways have instead been targeted in both preclinical and clinical studies. In this review, we discuss how the complexity of various tumor microenvironment (TME) components and the oncogenic signaling pathways that they are connected to actively contribute to the development and spread of PDAC, as well as the ways that recent therapeutic approaches have been targeted to restore it. We also illustrate how many endogenous stimuli-responsive linker-based nanocarriers have recently been developed for the specific targeting of distinct oncogenes and their downstream signaling cascades as well as their ongoing clinical trials. We also discuss the present challenges, prospects, and difficulties in the development of first-line oncogene-targeting medicines for the treatment of pancreatic cancer patients.