Bacteriophages as a Class of Vector for Future Targeted Senolytics
In this open access paper, the authors discuss the merits of bacteriophages to carry therapeutics to specific cell populations, offering targeting of senescent cells as a starting point. While they see bacteriophages as a way to displace existing viral vectors in the long run, clearly this will be a matter of decades from where things stand now, if it comes to pass. It is, nonetheless, an interesting look at a growing area of therapeutic development. Setting aside the question of senescent cells, a better general platform for carrying gene therapies to specific tissues, or throughout the body with high efficiency, is very much needed. Whether lipid nanoparticles, improvements to existing viral vectors, or some other technology such as engineered bacteriophages will satisfy that need at the end of the day is yet to be determined. Work proceeds on all fronts, at various stages of development.
Bacteriophages are viruses that are widespread in the environment because they occur wherever they find a suitable bacterial host to survive and multiply; thus, they are naturally present on and in the human body. Because of their selectivity to specific bacterial species, they are highly specialised in infecting bacteria and fighting bacterial infections. Interestingly, this selectivity is not accompanied by any harmful effects on human cells, which is probably the result of large interspecies differences. For this reason, various studies have used phages and their enzymes as alternatives to antibiotics to address dangerously increasing antibiotic resistance.
Several unique features of bacteriophages include the ability to integrate fragments of an exogenous nucleic acid into their genome and undergo easy chemical modification to display specific targeting and/or imaging ligands on the phage surface; because of such features, they may be used as new forms of modern high-performance vectors for therapeutic compounds and vaccine delivery. Bacteriophages can carry various types of cargo, including oligonucleotides, peptides, antibodies, proteins, carbohydrates, vitamins, drugs, fluorescent dyes, aptamers, siRNA, CRISPR-Cas, large mammalian gene expression cassette, synthetic polymers, photosensitizers, quantum dots and other small nanoparticles. It was demonstrated that the potential of phages as vectors is broadened by their good biocompatibility, homogeneity, thermodynamic stability, high load capacity, efficient self-organisation ability, and scalability.
Moreover, genetic engineering and/or chemical methods may enable the synthesis of a specially designed phage with the ability to target a specific surface marker of a senescent cell. The application of a preparation composed of one type of phages to the patient is called single therapy. As many types of senescent cells characterized by various surface markers are present in different tissues simultaneously, even more beneficial than single therapy, seems to be a combination therapy. Such therapy can be simultaneous and rely on the introduction at the same time of a mixture of several types of phages (so-called phage cocktail) as well as sequential, consisting of the application of different types of phages or their cocktails at fixed intervals.