## 4 Discussion
The use of these extracts and their encapsulation in NPs should not be studied as a possible isolated treatment route; their possible combination with chemotherapeutics such as 5-FU has also been observed to obtain a greater cytotoxic effect by reducing the amount of the drug used and, therefore, the possible side effects generated [44]. This possible synergy between plant extracts and chemotherapy drugs used in CRC is justified by the presence of different types of bioactive compounds in these extracts, such as curcumin, resveratrol and epigallocatechin gallate (EGCG), which have shown, in previous studies, their synergistic capacity with cytotoxic drugs such as 5-FU, doxorubicin, oxaliplatin, carboplatin or irinotecan [53; 54]. One of the major problems of the NPs studied is the absence of molecules that reduce the immunogenicity they generate in the blood. Thus, other authors such as [PERSON] et al. (2021) synthesized and characterized NPs based on hyaluronic acid (HA) and albumin capable of demonstrating high solubility, stability, biocompatibility, and absence of immunogenicity. In addition, functionalization with HA would grant them some selectivity against CD44 receptor, a characteristic lacking in the nanoformulations presented in this review [55]. This type of functionalization against CD44 is quite promising in the synthesis of new NPs, given that it is a receptor associated with a worse prognosis in CRC and that it is overexpressed in tumor stem cells in this type of tumor [56]. Other types of functionalization have been studied, which attempted to use antibodies, nucleic acids, vitamins or peptides to increase the interaction between nanoformulations and cells, allowing greater entry of the encapsulated pharmaceuticals and improving their therapeutic effect [57; 58]. In addition, the nanoformulations included in this review were also tested in other types of tumors; [PERSON] et al. (2021) demonstrated the performance of their nanoformulations on breast cancer and melanoma cells, while [PERSON] et al. (2020) additionally studied their nanoparticles on pancreatic and breast adenocarcinoma cells [29; 31]. Of the 17 articles finally selected in this review, in vivo experiments were performed in only two of them [23; 42]. Among them, we highlight the study carried out by [PERSON] et al. (2022), where the in vitro benefit of the encapsulation of the extract in nanoparticles was demonstrated and, additionally, a lower number and a smaller size of colon cancer precursor lesions were observed in a model generated in situ using AOM/DSS [42]. Thus, the loading of extracts in NPs produced an increase in antitumor efficacy in those assays in which in vivo models were used, since it favors the entry and deposition of NPs in the tumor tissue due to the increased retention and permeabilization effect (EPR), which, in addition to a defective lymphatic drainage, reduces the amount of concentration necessary to achieve the same tumor damage [59; 60]. Despite the interesting results obtained both in vitro and in vivo in the included studies, it should be noted that any nanoparticles based on plant extracts or natural compounds are currently in clinical trials. Thus, the nanoformulations currently in different phases are based on conventional chemotherapeutics, such as capecitabine, irinotecan, doxorubicin and 5-FU, or drug combinations such as FOLFOX [61]. The big problem with these formulations is the large number of side effects they generate in patients due to their lack of specificity; thus research is already underway to examine the ability of different plant compounds (such as flavonoids) to have a palliative effect on symptoms in combination with conventional chemotherapy [62]. Therefore, the nanoformulations synthesized and characterized in the studies included in this review would be potentially useful for the treatment of CRC, avoiding cellular resistance mechanisms such as efflux pumps [63].