The Chimera of TPGS and Nanoscale Lipid Carriers as Lymphatic Drug Delivery Vehicles to Fight Metastatic Cancers

The lymphatic system (LS) plays a crucial role in fluid balance, transportation of macromolecules, and immune response. Moreover, LS is a channel for microbial invasion and cancer metastasis. Particularly, solid tumors, including lung, breast, melanoma, and prostate cancers, are metastasized across highways of LS. Subsequently, the fabrication of chimeric lymphatic drug delivery systems (LDDS) is a promising strategy to fight cancer metastasis and control microbial pandemics. In this regard, LDDS, in terms of PEG-nanoscaled lipid carriers, elicited a revolution during the COVID-19 pandemic as cargoes for mRNA vaccines. The drug delivered by the lymphatic pathway escapes first-pass metabolism and enhances the drug's bioavailability. Ample approaches, including synthesis of prodrugs, trigging of chylomicron biosynthesis, and fabrication of nanocarriers, facilitate lymphatic drug delivery. Specifically, nanoscales lipid cargoes have the propensity to lymphatic trafficking. Interestingly, TPGSengineered nanoscale lipid cargoes enhance lymphatic trafficking, increase tissue permeation, and, specifically, uptake. Moreover, they overcome biological barriers, control biodistribution, and enhance organelles localization. Most anticancer agents are non-specific, have low bioavailability, and induced drug resistance. Therefore, TPGS-engineered nanoscale lipid chimeras improve the therapeutic impact of anticancer agents. This review highlights lymphatic cancer metastasis, nanoscales lipid cargoes as LDDS, and their influence on lymphatic trafficking, besides the methods of LDD studies.