Malignant tumors are a major problem threatening human health. Chemotherapy is one of the most important treatments for advanced malignant tumors (Bray et al., 2020). Chemotherapy refers to the use of one or more chemical drugs to inhibit tumor cell proliferation, infiltration and metastasis and ultimately kill cancer cells to cure the tumor. Many anticancer drugs (e.g., chemotherapy, biological therapies and hormones) have been developed to treat cancers; however, most chemotherapeutic drugs are not selectively distributed in tissues and have fast proliferation rates, thus affecting normal cells such as hair follicles, bone marrow and gastrointestinal tract cells. Hence, chemotherapy has serious toxic and adverse effects.

Nanomedicines were first developed in the 1960s (Wang et al., 2008; Zhao et al., 2014; Bray et al., 2020) when scientists proposed the application of nanolipid vesicles (i.e., liposomes) for drug delivery. Since then, many nanodrug delivery systems have been developed. The main developments of nanomedicines can be summarized as follows (Wang et al., 2018) (Figure 1). In 1976, Langer et al. first proposed a sustained-release drug delivery system (Langer and Folkman, 1976), and in 1980, Yatvin et al. designed liposomes with pH-responsive drug release and active targeting functions for drug delivery (Yatvin et al., 1980). In 1986, Matsumura and Maeda proposed the enhanced permeability and retention effect (EPR effect) (Figure 2), stating that nanomedicines can gradually accumulate at tumor sites and remain in the tumor tissue based on the pathological characteristics of tumor vascular discontinuity and an incompetent tumor lymphatic system (Matsumura and Maeda, 1986). Langer and Folkman prepared the first long-circulating poly (ethylene glycol)-poly (lactic acid-ethanolic acid) nanoparticles, which were approved by the U.S. Food and Drug Administration (FDA) as the first nanomedicine for clinical use in treating ovarian cancer, metastatic breast cancer, and acquired immunodeficiency syndrome-related Kaposi’s sarcoma (Langer and Folkman, 1976). Since then, many nanomedicines have entered clinical trials, and some have been approved to clinically treat tumors. Currently, 15 nanomedicines have been approved by regulatory agencies such as the FDA and the European Medicines Agency for treating cancer, and over 50 nanomedicines are in clinical trials. The clinically approved nanomedicines include ten liposomes, two polymeric micelles, two nanoparticles, and one inorganic nanoparticle, but no polymeric nanovesicles have yet received clinical approval (Table 1).

Lipids, inorganic nanomaterials, and polymers are often used in nanocarrier systems (Figure 3). Lipids are used as raw materials to prepare lipid-based nanocarriers because they have excellent biosolubility and can wrap both hydrophilic and hydrophobic drug molecules. Some lipids can also attach drug molecules to the nanoparticle surface via adsorption to improve the drug’s ability to enter cancer cells by adsorption or cell membrane fusion, which significantly improves the drug’s bioavailability. Inorganic nanocarriers are easy to prepare and easy to control in size and shape. The special properties of inorganic materials, such as their optical, electrical and magnetic properties, provide a favorable basis for their use in targeted tumor therapy, diagnostic imaging and targeted drug delivery. Gold, mesoporous silica, and magnetic nanoparticles are used in inorganic nanodrug delivery systems. Polymer-based nanocarriers are the most widely studied and valuable system in clinical practice. The material composition and structure of polymeric carriers include linear polymeric carriers, polymeric micelles and self-assembled nanovesicles.

Polymer nanovesicles are self-assembled and formed by amphiphilic polymers in aqueous solution; they are similar to liposomes, with a closed membrane and ordered structure (Mikos et al., 1994; Jiang et al., 2015; Wang et al., 2015). The self-assembly morphologies of polymeric nanovesicles and micelles differ primarily in the hydrophilic and hydrophobic ratios of the polymers that make up the micelles or nanovesicles. Polymeric nanovesicles, such as liposomes, can be actively loaded with weakly alkaline or acidic hydrophilic drugs (e.g., doxorubicin hydrochloride) via ionic gradients (e.g., pH, ammonium sulfate, and calcium acetate gradient) and can be loaded with biomolecules via electrostatic or hydrogen bonding interactions. The thicker and tunable hydrophobic membranes of polymeric nanovesicles can be used to treat and diagnose cancer by loading hydrophobic drugs or fluorescent probes through hydrophobic interactions (Kim et al., 2009; Wang et al., 2015; Phan et al., 2021; Shreyash et al., 2021).

Despite the many advantages of polymeric nanovesicle carriers, no nanovesicular drugs have received FDA approval or are in clinical trials. Here, we review the progress in this emerging new drug system by first summarizing the properties of polymeric nanovesicles, then discussing their preparation methods. Next, we present the applications and recent research progress regarding polymeric nanovesicles as nanodrug carriers in therapeutics, including prolonged tumor retention, reversal of multidrug resistance, inhibition of tumor metastasis, prevention of tumor recurrence, and novel smart polymeric nanovesicle carrier antitumor drugs. Finally, we review the prospects and challenges of polymeric nanovesicles as nanocrushed carriers in cancer clinical therapy (He et al., 2019; Pearce and O’Reilly, 2019; Saha et al., 2019)

Polymeric nanovesicles are vesicular cavity spheres or spheres with a liposomal bilayer structure formed via self-assembly of amphiphilic block copolymer molecules in water (Discher et al., 1999). The structure is specialized, with a hydrophilic inner cavity and hydrophobic membrane layer, while the outer surface of the membrane layer also has a hydrophilic shell, thus constituting a hydrophilic-hydrophobic-hydrophilic cavity-membrane-shell structure from the inside to the outside of the formation. Because the particle size can be controlled, polymeric nanovesicles offer both the advantages of nanoparticles and the unique advantages created by their specialized structure. Their characteristics are summarized below.

Polymeric nanovesicles are unique drug carriers with a hydrophilic lumen that can solubilize water-soluble active ingredients and a hydrophobic membrane layer that can solubilize lipid-soluble drugs. Polymeric nanovesicles can carry both these active ingredients simultaneously. The larger hydrophilic lumen facilitates encapsulation and protection of water-soluble biomolecules (e.g., drugs, peptides, proteins, enzymes, and RNA and DNA fragments) (Christian et al., 2009). The thicker hydrophobic membrane layer facilitates loading and solubilization of lipid-soluble drugs (e.g., paclitaxel) (Li et al., 2007). Polymeric nanovesicles do not need to change the structures of the drug molecules or biomolecules, such as proteins, to protect them from degradation and inactivation of their active ingredients, improve the drug stability, and enhance their efficacy and pharmacological properties.

Polymeric nanovesicles have a double membrane-layer structure that is similar to biological membranes and is more compatible with the drugs being delivered, thus making them good drug-delivery carriers in vivo. This double membrane layer can help the drug cross the biological barrier, change the drug’s distribution in the organism and reduce systemic toxic adverse effects (Santos-Magalhães and Mosqueira, 2010; (Xiong et al., 2011). The thicker double-layer structure of the vesicles increases the time needed for active molecules to enter and leave the vesicles, which can prolong the drug-release time, stabilize the blood concentration and improve the drug’s bioavailability. The hydrophilic shell structure of the outer layer enhances the spatial stability of the vesicles, prolongs the circulation time of the vesicles in the body, and further improves the drug’s bioavailability (Singh and Lillard, 2009; Alibolandi et al., 2016).

Because the particle size of polymeric nanovesicles is only a few hundred nanometers and has long circulation characteristics in vivo, drug-carrying vesicles can use the EPR effect of tumor cells to accumulate spontaneously through the permeable vascular tissue at the lesion site and obtain passive targeting ability (Photos et al., 2003). The EPR effect promotes selective enrichment of the nanovesicles and other macromolecular particles in cancerous tissues, which increases the blood concentration and improves the therapeutic efficacy. This increases the blood concentration of the drug at the site, improves the drug’s efficacy and reduces the systemic toxic adverse effects.

Specific ligands, such as antibodies, peptides, galactose, mannose and folic acid, can be stably attached to the surface of polymeric nanovesicles to confer active targeting functions and other biological effects on the vesicles. When receptors on the surfaces of target cells specifically recognize and bind ligands, the ligands can effectively mediate endocytosis vesicle into target cells and deliver more drug to the target cells while overcoming the nonspecific clearance of the reticuloendothelial system, improving the killing of target tissue cells, and reducing the toxic adverse effects to other cells.

Polymeric nanovesicles have good molecular designability. Selecting different amphiphilic polymers enables subjectively controlling the physicochemical properties (e.g., particle size, zeta potential, membrane thickness, elasticity, degradability, stimulus responsiveness, permeability, and drug-loading capacity) (Torchilin et al., 2003; Lin et al., 2006; Sutton et al., 2007; Danhier et al., 2010; Pawar et al., 2013) and the in vivo mode of action of the constructed vesicles. Polymeric materials with good biodegradability, whose degraded products are nontoxic or less toxic and can be excreted through normal physiological metabolism, are typically used to prepare vesicles to avoid long-term accumulation of toxic adverse effects. Differences in the tumor tissue and normal tissue microenvironments enable constructing vesicles using polymeric materials that respond to stimuli, which in turn makes the vesicles more responsive to stimuli (Zhang et al., 2012). These polymeric nanovesicles are stable when circulating in vivo, and when they reach the targeted lesion, they respond to a specific stimulus at that site by changing the properties of the polymeric chain segments and rapidly releasing their encapsulated drug or bioactive molecule at that specific site. Polymeric nanovesicles can respond to stimuli such as acidity, temperature, redox, enzymes, light, and magnetic fields. This enhances the targeting effect of the nanovesicles, enriches the vesicles at the target site, promotes cellular uptake of the vesicles and drug, improves the drug’s therapeutic effect, prevents toxic adverse effects to normal tissues or organs due to premature drug release, and prevents development of drug resistance due to slow release of the drug and nanovesicles at the target site.

Polymeric nanovesicles are commonly synthesized via film hydration, solvent volatilization, phase transfer, direct dissolution, electrical formation and microfluidic preparation (Liao et al., 2012; Shen et al., 2017).

In film rehydration, the amphiphilic polymer is completely dissolved in a volatile solvent, then the solvent is fully removed using a rotary evaporator to form a polymer film and vacuumed until completely dry. Water is then added to hydrate it. During hydration, water molecules penetrate the film, causing the hydrophilic chain segments to extend toward the aqueous phase, while the hydrophobic chain segments aggregate into a film layer and self-assemble into larger polymer nanovesicles.

In the solvent volatilization method (solvent evaporation), the amphiphilic polymer is fully dissolved in a volatile organic solvent, added dropwise to the aqueous phase while stirring, then continuously stirred to remove the organic phase, i.e., the polymer nanovesicles with a more uniform particle size distribution.

In the phase-transfer method (phase transfer), the amphiphilic polymer is fully dissolved in the organic solvent, which is miscible with water, then added dropwise to the aqueous phase while stirring to produce the polymer nanovesicles. This method allows subjectively regulating the size and distribution of the nanovesicles via the different solvents used.

In the dialysis method (dialysis), the amphiphilic polymer is fully dissolved in an organic solvent that is miscible with water, and the organic phase is purified by dialysis to obtain polymer nanovesicles.

In direct formation, amphiphilic polymers with a low glass-transition temperature are added to the aqueous phase and thoroughly mixed to produce the polymer nanovesicles. Water-soluble amphiphilic polymer materials that respond to external stimuli can be directly dissolved in the aqueous phase allowing the polymeric nanovesicles to self-assemble by controlling the pH or temperature of the aqueous phase.

Using electroformation, the polymer film is first formed on a cobalt wire electrode, then the electrode is combined with a Teflon shelf in a sealed chamber injected with sugar water. A suitable electric field is applied to the electrode, and the vesicles gradually form on the film surface after 15–60 min. After reducing the electric field intensity, the vesicles can be removed from the electrode.

Microfluidic fabrication is a newly emerging method for preparing polymeric nanovesicles. Compared with other methods, substances of large molecular weight can be effectively loaded to form large, uniformly distributed polymeric nanovesicles. This method uses the principle of W/O/W double emulsification to form a monodisperse W/O/W double-emulsified structure in a glass capillary, which is then placed under ventilation to allow the organic solvent to evaporate to obtain the polymeric vesicles (Lopresti et al., 2009).

Polymeric nanovesicles are typically used as submicron hollow spherical structures, with the main structure composed of a polymer shell and hollow inner space (Tang et al., 2016). The nanovesicle cancer drug delivery system reduces adverse effects, improves treatment efficiency, and reduces the administration frequency (Figure 4). In this section, we introduce the latest progress in preparing nanovesicles and their applications as antitumor drug delivery carriers. We also introduce some newly emerging nanovesicles with potential for cancer drug delivery.

Drug delivery is an important application of polymer nanovesicles. Knowledge of cancer nanomedicine has drastically improved in recent decades. However, most approved nanomedicines have used existing drugs as payloads, and the use of small molecules for chemotherapy remains unsatisfactory. This review summarized the advances in polymer nanovesicles from the aspects of synthesis, preparation, multifunctions and applications. Polymeric nanovesicles have unique advantages over other polymersomes. Their specialized structures and properties exhibit good stability and permeability, easy functionalization, and smart stimulus responsiveness. These advantages make them one of the most promising supramolecular structures for potential applications in delivering drugs, genes and other therapeutic substances. Additional applications in immunotherapy, especially biomedical applications such as drug delivery and gene therapy, should be explored to promote the development of polymer nanovesicles.