Nelson C. Soares

The use of poly(lactide‐ co ‐glycolide) (PLGA) nanoparticles (NPs) as carriers for chemotherapeutic drugs is regarded as an actively targeted nano‐therapy for the specific delivery of anti‐cancer drugs to target cells. However, the exact mechanism by which PLGA NPs boost anticancer cytotoxicity at the molecular level remains largely unclear. This study employed different molecular approaches to define the response of carcinoma FaDu cells to different types of treatment, specifically: paclitaxel (PTX) alone, drug free PLGA NPs, and PTX‐loaded PTX‐PLGA NPs. Functional cell assays revealed that PTX‐PLGA NPs treated cells had a higher level of apoptosis than PTX alone, whereas the complementary, UHPLC‐MS/MS (TIMS‐TOF) based multi‐omics analyses revealed that PTX‐PLGA NPs treatment resulted in increased abundance of proteins associated with tubulin, as well as metabolites such as 5‐thymidylic acid, PC(18:1(9Z)/18:1(9Z0), vitamin D, and sphinganine among others. The multi‐omics analyses revealed new insights about the molecular mechanisms underlying the action of novel anticancer NP therapies. In particular, PTX‐loaded NPs appeared to exacerbate specific changes induced by both PLGA‐NPs and PTX as a free drug. Hence, the PTX‐PLGA NPs’ molecular mode of action, seen in greater detail, depends on this synergy that ultimately accelerates the apoptotic process, resulting in cancer cell death.