According to recent estimates, cancer represents the first or second highest cause of death in most countries around the world, with nearly 10 million deaths globally reported in 2020 (WHO). Moreover, a dramatic increase in the number of new cancer cases is expected over the next decades, with an increase of 47% from 2020 to 2040 
. The high prevalence of cancer and its increase is due to the aging/growth of the population and to risk factors that continue to represent the predominant cause of cancer in many countries (such as tobacco smoking in Western countries or viral infection in developed countries) or that are escalating all over the world (such as overnutrition and overweight) 
. It is noteworthy that the same risk factors associated with cancer (chronic infections, tobacco smoking and chronic alcohol abuse, chronic pollutant inhalation, overnutrition and obesity, and autoimmunity) are also related to chronic inflammation 
. This is in keeping with the close connection existing between chronic inflammation and cancer since, on the one hand, chronic inflammation may precede and be strictly related to both tumorigenesis and cancer progression. On the other hand, the tumor itself may intrinsically induce an inflammatory response, and, in the long term, the recruited inflammatory cells can also create an immunosuppressive environment able to facilitate the progression of cancer 
. This explains why factors able to negatively regulate the inflammatory response are considered important tools in the prevention of cancer and may also exert important roles in the treatment of cancer.
2. PheCs Included in Drug Nanodelivery Systems for Tumor Targeting
Among the bioactive natural products investigated for reinforcing the anticancer effects of chemotherapy treatments and recently included in a series of nanodelivery systems developed for tumor targeting. They are characterized by the presence of at least one phenol ring in their moiety and are well known for their powerful anti-inflammatory, antioxidant, and anticancer properties 
. In particular, plenty of results obtained both in in vitro and in vivo have supported the powerful effects that a series of PheCs may exert against the development and progression of a variety of cancers 
. The antineoplastic activities have been described for compounds belonging to all the classes of PheCs 
. In fact, this represents the most numerous group among the phytochemicals present in fruits, vegetables, and other foods 
, and, according to version 3.6 of the Phenol-Explorer database regarding the polyphenol content in foods 
, there are over 500 PheCs present in our diet that can be classified in different classes. The most numerous class is that of flavonoids
, which, according to this classification, includes 279 compounds present in our diet, divided into the sub-classes of anthocyanins, chalcons, dihydrochalchones, dihydroflavonols, flavanols, flavanones, flavones, flavonols, and isoflavonoids (Figure 1
are polyphenolic compounds grouped in a single class on the basis of their common 15-carbon skeleton formed by two benzene rings (A and C, see Figure 1
) bound together by a heterocyclic pyrane ring (B in Figure 1
). They are ubiquitously found in plants, where they play a role in response to microorganism infections 
. Their recognized antioxidant and free radical scavenging activity is mediated by the hydroxyl groups bound to their phenolic rings. These hydroxyls are also able to chelate metal ions and, thus, hamper the metal-catalyzed generation of reactive oxygen substances (ROS) and their oxidant activity. According to the research of the literature, the flavonoids
that have been included in HA-coated delivery nanosystems investigated against cancer in the last 5 years are the two flavonols:
and quercetin (QU) 
, the flavanol
epigallocatechin-3-gallate (EGCG) 
, the isoflavone
, and a mix of anthocyanins
extracted from corn 
Classes of natural dietary phenolic compounds (PheCs) according to the version 3.6 of the Phenol-Explorer database regarding the polyphenol content in foods (http://phenol-explorer.eu/compounds
, accessed on 24 March 2023).
Between brackets are reported the number of compounds belonging to each class or subclass according to this classification. In red are the PheCs that have been included in HA-coated delivery nanosystems and investigated in the last 5 years: 2018–2023.
The major non-flavonoid
subclass for numerosity is that of the phenolic acids containing over 100 compounds present in our diet (Figure 1
). They include in their moiety a single phenolic ring with an organic carboxylic acid bound to it. They have been further divided into different subgroups, among which hydroxybenzoic acid and hydroxycinnamic acid groups are the most prevalent. Phenolic acids are widespread in foods and contribute to their organoleptic characteristics (color, flavor, astringency, and harshness) as well as to their nutritional properties. In fact, similarly to what was observed for the compounds belonging to the class of polyphenols flavonoids
, they exert antioxidant activities and have been observed to protect from neurodegeneration 
. Moreover, they may induce many other health benefits, including the prevention of neoplastic, metabolic, and cardiovascular diseases 
. The only phenolic acid included so far in an HA-coated delivery system for the targeting of cancer is gallic acid 
, which belongs to the class of hydroxybenzoic acids. Other phenolic acids (dihydrocaffeic acid, ellagic acid), however, were recently included in HA-based NPs for preventing degenerative or inflammatory conditions known to be pro-carcinogenic, such as those induced by UVB radiations 
or associated with chronic inflammatory bowel diseases 
. Moreover, gallic acid was also included in an HA-based immunosuppressive hydrogel for possible applications in wound healing and tissue regeneration 
Then, according to the same classification, among the dietary PheCs have also been included the 2 less-abundant groups of the Stilbenes
), and finally, under the name of Other Polyphenols
, a series of 80 compounds among which there is the curcuminoid
curcumin (CUR), which has been largely reported to have a prominent antioxidant and anticancer activity 
). In particular, stilbene
are the non-flavonoids
that have been so far included in HA-coated delivery systems for possible cancer targeting.
For their presence in our diet, PheCs are generally considered safe and usable, with no trouble for the design of new drugs. However, it should be underlined that PheCs may interact and interfere with many currently used conventional drugs, making their use not completely devoid of risks for some classes of patients 
. In particular, Gómez-Garduño et al. 
reported that the interactions of PheCs with drugs often involve cytochrome CYP3A enzymes and P-gp transporters and are mediated through the regulation of gene expression or inhibitory effects on functional proteins that, ultimately, may modify plasma concentrations of drugs. These interactions are presumably related to the distribution of phytochemicals in circulation and, from there, to all our organs and tissues. This underscores how useful and safe it may be for therapeutic scopes, introducing these bioactive natural compounds not in a free form but included in drug-delivery systems, which, besides protecting them from unwanted chemical interactions, may mainly and specifically transport them to tissues where pathologic processes are ongoing.
As indicated above, the researchers are here restricting the critical analysis to papers focused on the improvement of anticancer chemotherapy obtained through the inclusion of PheCs in delivery systems. However, the researchers are excluding those papers focusing on nanoformulations that include PheCs not on the basis of their recognized antitumor effects but just for their ability to bind firmly to other molecules and form an envelope able to include and protect and/or more easily release the anticancer drugs in the tumor environment. In fact, for instance, due to their ability to self-assemble to metals, PheCs can form the metal-phenolic networks (MPNs) that have recently received considerable attention for their possible biological applications as coating materials suitable not only for drug delivery but also for the improvement of bioimaging and encapsulation of cells 
. These coatings are quickly and easily obtained by mixing a PheC and a metal cation in the presence of a substrate. Therefore, for these applications, PheCs are used only since they contain aromatic rings with hydroxyl groups, which may serve as multivalent chelation sites able to interact with metal ions, thus giving the possibility of forming a coating network on a variety of substrates independently from their features, surface charge, or shape 
. In particular, PheCs that contain dihydroxyphenyl (cathecol) or trihydroxiphenyl (galloyl) groups can be used for interface engineering and particle development, thanks to the possibility of establishing through them covalent and non-covalent interactions needed for the assembly of PheC-based materials 
. On the other hand, some PheCs, such as anthocyanins, have also been used as promising nanovectors for chemotherapic drugs, and not on the basis of their known powerful anticancer properties 
. For instance, in a recent study by Xiong et al. 
, the flavonoids
anthocyanins were used as vectors in NPs designed for the delivery of the antineoplastic drug doxorubicin to colon cancer cells. In this case, the anthocyanins were one of the components of the hydrophobic core of the nanosystem, and for their property of being ROS-responsive, they had the potential to break the covalent bonds to allow the preferential release of the covalently linked drug in the ROS-enriched tumor microenvironment.
3. Hyaluronic Acid: An Efficient Carrier for the Specific Delivery of Antineoplastic Drugs and Natural Bioactive Products
As indicated above, the researchers are here concentrating on the results of recently published papers focused on the hyaluronic acid (HA)-based delivery of PheCs to tumor tissues. Multiple properties of HA make this polysaccharide a particularly efficient platform for the specific delivery of antineoplastic drugs and natural bioactive anticancer therapeutics. In fact, it is constituted by repeating units of the disaccharide D-glucuronic acid and N-acetyl-D-glucosamine, and it is naturally synthesized by our body. It represents a main constituent of the extracellular matrix and a ubiquitous component of our tissues 
, where it exerts crucial roles in some cellular processes, such as growth, differentiation, and migration 
. Altogether, this is enough to explain its high biocompatibility and lack of toxicity or immunogenicity. These features are crucial when considering its possible drug-delivery application. In fact, most synthetic polymers and inorganic materials that have been so far explored for this use have limitations, such as non-negligible in vivo toxicity 
. However, additional reasons make HA particularly attractive as a drug-delivery carrier, such as its biodegradability, as HA is degraded by multiple enzymes in the microenvironment of tumors, thus allowing easy release 
. Moreover, other critical reasons for its use in nanoformulations are its ability to be easily chemically modifiable and its hydrophilic properties, which make it particularly apt to transport hydrophobic drugs 
. In addition, it shows a high affinity for the cluster of differentiation-44 (CD44), a transmembrane glycoprotein that, besides participating in physiological processes, including cellular adhesion and migration in inflammation and repair 
, has been found to be overexpressed on the surface of a variety of cancer cells, particularly in solid tumors such as breast, cervical, and prostate cancer and glioblastoma 
. This receptor was found to be significantly upregulated in cancer stem and metastasizing cells, representing a biomarker of cancer cell stemness 
or epithelial–mesenchymal transition 
. In fact, it has been involved in the survival of stem cells, as well as in invasion, metastasis, neoangiogenesis, and drug resistance and recurrence 
. This means that a delivery system coated with HA has the potential to reach specifically the stem cells inside the primary cancer, as well as the metastases spread from it. Finally, it has been reported that CD44 could play not only the role of a “binder” for a ligand such as HA but also that of an “internalizer”, thus facilitating not only the specific targeting of cancer cells by HA-coated drug systems but also improving their endocytosis and accumulation inside the target cells, thus enhancing the antitumor efficacy of the delivered drugs 
. Altogether, this means that the HA-containing drug-delivery systems, due to their ability to bind with high affinity to the CD44 receptor on cancer cells, could have the potential to overcome the remarkable systemic side effects usually induced by most antineoplastic chemotherapeutic drugs characterized by a very poor tissue specificity.
There are different forms of HA-based delivery systems that have been designed and used for a more specific, efficient, and safe cancer therapy. The simplest and largely used way to specifically carry an anticancer agent in combination with HA is to conjugate it to the HA moiety itself. For instance, it has been largely shown that conjugation of HA with several anticancer drugs (such as paclitaxel, taxol, CPT11) can significantly increase the growth-inhibiting effect of the drugs in CD44-overexpressing cells, including breast, colorectal, esophageal, gastric, lung, and ovarian cancer cells (for a review, see 
). Moreover, drug conjugation with HA allows for enhancing the water solubility of scarcely soluble drugs.
Moreover, HA has been used to form both inorganic and organic nanostructures. Among the last, there are amphiphilic polysaccharide polymeric micelles, where HA can function both as a hydrophilic polymer forming the external part and as a ligand for targeting CD44 that is overexpressed on many cancer cells 
. Liposomes, which can encapsulate both lipophilic drugs in the lipid bilayer and hydrophilic drugs in the aqueous core, have also been often decorated with HA to make the targeting cancer specific. Similarly, HA-decorated nanoparticles of different kinds, as well as HA-decorated nanogels, have been extensively used for more specific delivery of chemotherapeutic drugs (for a review, see 
). HA-based nanogels have also been designed, where HA represents a constituent of the matrix encapsulating the drug.