Besides its use as a nanocarrier, albumin can be used as a coating agent for a variety of nanostructures, thus the advantages mentioned before on the use of albumin can be implemented to other nanostructures [51,76,77]. In a study conducted by Xu and co-workers, a chitosan complex with siRNAs was coated with pH-responsive detachable BSA to enhance recognition by human hepatocellular carcinoma cells and suppression of tumor cell proliferation [77]. In this case, the mRNA silencing obtained by the chitosan NPs was improved from 46.9% to 61.8% by the introduction of a BSA coating.

Albumin has been used as a coating agent in various lipid-based nanocarriers, to minimize their interaction with serum proteins and improve their delivery to the target sites [51,78]. For instance, HSA was used to coat lipid nanoparticles loaded with siRNA targeted against GFP (HSA-LNPs-siRNA) and their activity was evaluated in breast cancer cells and the corresponding xenograft mouse model [51]. In the cell experiments, the nanoparticles containing HSA significantly reduced the GFP fluorescence, compared to uncoated lipid nanoparticles. This result was also obtained in the animal model, where a 37% reduction in the GFP expression was achieved after systemic administration of the HSA-coated nanoparticles. In another study, HSA was employed to coat lipid nanoparticles loaded with an antisense oligonucleotide against Bcl-2, which were evaluated in KB human oral carcinoma cells [78]. Interestingly, the authors reported that the efficiency of the Bcl-2 down-regulation depended on the molar ratio of HSA employed. The optimum down-regulation was observed with an HSA to liposome ratio of 3:100 after which the increment in HSA decreased the efficiency.

Cancer immunotherapy aims to exploit the patients’ own immune systems to treat cancer. Some of the approaches to cancer immunotherapy include immune checkpoint blockade, cancer vaccines, adoptive cell transfer therapy, and oncolytic virotherapy [79]. Among all, immune checkpoint inhibitors have gained wide success in cancer treatment, however, only a limited number of patients benefit from these therapies, where the induction of resistance and toxicity are still huge problems [80]. Interestingly, nucleic acid therapeutics are emerging as the potential candidate for cancer immunotherapy, which may improve the therapeutic outcome in a wide range of tumors, and even in the late stages [81]. These nucleic acids include immunostimulatory DNA/RNA, genome editing nucleic acids, and mRNA/plasmid, which can be further translated to immunotherapeutic proteins [82]. In addition, different genetic tools such as gene editing, gene silencing, or gene activating systems are also being studied extensively in cancer immunotherapy [81]. Nonetheless, despite the tremendous potential of nucleic acids in cancer immunotherapy, the major limitation in the implementation of these techniques in clinical practice is the lack of an efficient delivery vehicle targeted to the cancer cells. In this context, albumin-based nanocarriers are being investigated in a variety of cancers. For instance, Cheng and co-workers developed HSA NPs complexed with stearyl PEI (stPEI), which was non-covalently bound to plasmid (CRISPR/Cas9) and a siRNA that silenced the expression of programmed cell death ligand-1 (PD-L1) for cancer immunotherapy [53]. This combined approach produced a synergistic effect where the PD-L1 expression was inhibited by 21.2%.

In summary, immunotherapy against cancer mediated by nucleic acids has enormous potential, as highlighted by the recent developments, such as chimeric antigen receptors (CARs), to treat leukemia (e.g., Kymriah [83]), or CRISPR/Cas9 approaches employed to enhance T-cell mediated gene therapy [84]. However, such systems can be further improved by nanocarriers, such as those based on albumin.

6. Conclusion

In conclusion, albumin nanocarriers have been studied widely for gene therapy in cancer because of the unique features of albumin, such as the ease of preparation, high stability, and biocompatibility. Furthermore, the surface of those nanocarriers can be modified to enhance the therapeutic efficiency and selectivity, whereas reducing the undesired off-target effects. Despite all those features, some limitations are still being reported and need to be addressed properly, such as the albumin catabolism, which may be affected by various factors such as the levels of corticosteroids. Therefore, further studies are required to ensure the safe use of those nanocarriers to ease their way to the clinic.

In addition to the prevalent conventional gene therapy, which is mainly focused on the expression of a DNA fragment or its random insertion into the genome, various specific gene-editing tools such as CRISPR/Cas9 have been introduced. These gene-editing tools have promising potential for the introduction of personalized medicines in cancer therapy. In a similar way, novel nucleic acid-based therapies such as chimeric antigen receptor (CAR) T approaches are being developed as a promising therapeutic approach in immuno-oncology. The combination of the advantages imparted by the albumin-based nanocarriers with powerful therapies including CRISPR/Cas9 and CAR-T will revolutionize the treatment options in oncology. Though there are limited studies available on the incorporation of these gene-editing tools in albumin nanostructures, the profound therapeutic application of these vectors is on the near horizon.