The EV-phage Biobots – unraveling natural synergies of extracellular vesicles and bacteriophage as a multifunctional therapeutic agent for infected skin wounds

Abstract

This research program aims to develop multifunctional biobots that integrate antimicrobial bacteriophage and cell-instructive EVs delivered precisely to an infected site where they synergistically kill bacteria and disrupt biofilm while modulating harmful inflammation and promoting tissue repair.Both phage and EVs have unique potential in treating infected wounds. Phage shows promising results in eliminating harmful bacteria and penetrating biofilm. EVs have demonstrated potential to reduce oxidative stress, activate the immune system and promote tissue regeneration. EVs have also demonstrated that they can simultaneously activate multiple cells, including stem, progenitor, and immune cells. This means that EVs stimulate the body’s immune system, working collectively with phage to overcome infection and inflammation. To achieve superior antimicrobial and anti-inflammatory activity, phage and EVs must be conjugated. Taken together, these findings led to establishing a technology to combine EVs and phage and for the first time to bioengineer new multifunctional biomaterial – the EV-phage biobots – with pre-defined molecular composition to achieve effective antimicrobial activity and promote tissue repair simultaneously. Phage have high and specific antimicrobial activity and can be employed as a carrier system for selectively delivering the EVs to the damaged tissue. Advantageously, the phage-EV conjugate provides targeted dual activity since EVs can target specific tissues or organs as well. The phage component of the phage-EV conjugate is capable of preventing and/or treating bacterial infection at a damaged tissue site, thereby reducing impaired tissue repair associated with infection. The EV component of the phage-EV conjugate promotes tissue repair. Administering an EV using a phage-based carrier can allow for potentially controlled, site-specific delivery of the EV, thereby achieving therapeutic local concentration at the site of the damaged tissue or infection.