## 9 Conclusions  
Gastrointestinal cancers are among the most prevalent and lethal malignancies worldwide, for which treatment is often compromised by the development of MDR. MDR is a complex phenomenon where cancer cells become resistant to a broad spectrum of chemotherapeutic agents, primarily due to the overexpression of ABC transporter proteins. These proteins, such as P-gp, MRP1/ABCC1, MRP2, and breast cancer resistance protein (BCRP/ABCG2), can act as efflux membrane pumps, expelling chemotherapeutic drugs from cancer cells and reducing their cytotoxic efficacy and antimuoral capacity. Although there have been decades of research and the development of MDR modulators, they still have limited efficacy, off-target effects, and toxicity. This issue requires an improvement in therapeutic responses with the development of new strategies. Plant-derived molecules offer a promising and versatile solution. Different compounds such as flavonoids, alkaloids, terpenoids, and coumarins have shown significant potential in modulating MDR mechanisms. These natural products can inhibit the activity of ABC transporters, downregulate their expression, and disrupt the signaling pathways ligated to them. For instance, flavonoids such as quercetin and kaempfer pol competitively bind to ABC transporter binding sites, reducing drug efflux and enhancing intracellular drug retention. Similarly, para-benzoquinones like embelin have shown the capacity to reverse MDR by targeting both transporter activity and cancer cell survival pathways. This natural strategy potentiates the effectiveness of standard chemotherapeutic therapies while minimizing toxicity to normal cells. Nanoplatforms, including liposomes, dendrimers, polymeric nanoparticles, and micelles, offer advanced drug delivery systems designed to overcome the limitations of traditional therapies. These nanocarriers provide several benefits, such as enhanced solubility of hydrophobic drugs, improved drug stability, controlled release, and selective tumor targeting. When used in combination with plant-derived molecules, nanoplatforms can co-deliver chemotherapeutic agents and MDR modulators directly to tumor cells, circumventing the efflux mechanisms of ABC transporters. Moreover, nanocarriers can be functionalized with ligands specific to tumor-associated markers, ensuring precision delivery while sparing healthy tissues. This targeted approach not only improves the therapeutic efficiency of anticancer drugs but also reduces systemic toxicity and off-target effects. For example, nanoparticles loaded with both 5 FU and GEM and a cardiotonic steroid, such as bufalin, as an MDR modulator have shown synergistic effects, significantly increasing drug accumulation within cancer cells and promoting apoptosis. The integration of plant-derived molecules with innovative strategies based on nanotechnology represents a paradigm shift in the management of gastrointestinal cancers. While preclinical studies are encouraging, challenges remain, including large-scale production, regulatory approval, and validation in clinical trials. Addressing these hurdles will be critical to translating these promising strategies into routine clinical practice. In conclusion, the combination of plant-derived compounds, such as quercetin, kaempfer, and embelin, with nanoplatforms, mainly polymeric nanoparticles, liposomes,and dendrimers, offers a synergistic approach to overcoming MDR in gastrointestinal cancers. By targeting the underlying mechanisms of drug resistance and enhancing drug delivery, this strategy has the potential to improve treatment efficacy, reduce toxicity, and ultimately enhance patient outcomes. Continued research and innovation in this field could lead to significant advancements in cancer therapeutics, offering hope to millions affected by these challenging malignancies. Conceptualization, C.M. (Consolacion Melguizo) and J.P.; methodology, G.P. and C.M. ([PERSON]); software, F.Q. and A.C.; validation, F.Q. and J.R.-C.; investigation, G.P., C.M. ([PERSON]), K.D. and M.P.