Living Microrobot for Active Therapeutic Delivery to Treat Severe Pulmonary Infections

About This Grant

Project Summary Multidrug-resistant (MDR) lower respiratory tract infections represent the single leading cause of infectious disease-associated mortality in the United States. Particularly worrisome trends are being observed in the case of ventilator-associated pneumonia (VAP), which affects vulnerable patient populations in intensive care units (ICUs). Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) are the most common causative agents in global epidemiology of VAP, and they are becoming increasingly prevalent as antibiotics continue to be used indiscriminately and with waning effectiveness. It is imperative that more effective treatment modalities be advanced to adequately manage serious pulmonary infections in the clinical setting. Here we describe a highly innovative delivery and therapeutic concept, living microrobot therapeutics, for critically ill patients with severe P. aeruginosa and MRSA lung infections. The microrobot platform is consisting of Chlamydomonas reinhardtii microalgae modified with neutrophil membrane-coated and drug-loaded polymeric nanoparticles (denoted ‘algae-NP-robots’), and has unique multifold mechanisms of action. The microalgae help to improve tissue penetration and retention of the drug payload within the lungs, while the neutrophil membrane- coated nanoparticles help to shield the drug payload from biological environments, reduce immune clearance, and enable specific binding with target pathogens. Besides carrying drug payload, the neutrophil membrane- coated nanoparticles can further serve as ‘nanosponges’ that act to neutralize excessive pro-inflammatory cytokines, thus reducing the danger of cytokine storm. By combining the unique properties of these two systems, the algae-NP-robots have proven to be a capable platform for active drug delivery and excel at treating bacterial pulmonary infections. In this proposal, we describe our extensive prior published and preliminary results that strongly support the novel therapeutic concept of algae-NP-robots for the treatment of severe Gram-negative and Gram-positive pulmonary bacterial infections in ICU patients. In Aim 1, we will focus on further optimizing the algae-NP-robot formulation to maximize its therapeutic potential. In Aim 2, we seek to better understand the mechanisms by which drug-loaded algae-NP-robots can effectively clear bacterial infection using P. aeruginosa lung infection model, in which efficacy has already been demonstrated. In Aim 3, we will extend the algae-NP- robot platform for the treatment of Gram-positive pathogen (MRSA) lung infection in order to demonstrate the generalizability of the platform. Each of the Aims can be completed independently, although the information gleaned from one can be used to improve the overall approach, which can then benefit the others.