Microbial infections pose significant therapeutic challenges due to rising antimicrobial resistance and limited availability of effective antimicrobials. Microbial species like Staphylococcus bacteria and Candida fungi are particularly problematic, with their ability to form biofilms that are extremely difficult to treat. Here, we will describe several unique nanoparticle drug delivery systems that exhibit excellent antimicrobial activity against infections caused by these microbes.

We have developed stimuli-responsive antibiofilm gelatin nanoparticles (R-GNPs) that release encapsulated silver nanoparticles as a broad-spectrum antibiotic alternative, in response to gelatinases secreted by biofilm-forming bacteria. Deoxyribonuclease I was conjugated to the gelatin nanoparticle core, leveraging its ability to degrade extracellular DNA, a key structural component of the Staphylococcus biofilm matrix. We further modified the nanoparticles with a pH-degradable poly(ethylene glycol) derivative, which ensures that the DNase becomes accessible within the acidic biofilm microenvironment. After confirming the dual-stimuli responsive mechanism of R-GNPs and in vitro efficacy, we found that treatment with R-GNPs led to a 99.9% reduction in Staphylococcus aureus in a murine excisional wound biofilm infection model compared to untreated controls.

To address Candida infections, we developed a Candida targeting liposomal nanoparticle functionalized with the cell-penetrating peptide, penetratin (Pen). We found that Candida albicans and Candida auris exhibited an ~80% interaction rate with Pen-decorated nanoparticles compared to 50% with non-Pen decorated nanoparticles. Upon loading with the fungistatic drug, posaconazole, we found an up to 1,300× reduction in the amount drug needed to inhibit Candida biofilms when treating with the Pen-decorated liposomes compared to free posaconazole. Prophylatic treatment with posaconazole-loaded Pen liposomes in a murine intradermal C. albicans infection model led to a ~60% reduction in fungal burden compared to treatment with a non-Pen decorated liposome.

Together, these nanoparticle formulations offer enhanced efficacy against difficult-to-treat microbial infections and have the potential to greatly improve future patient outcomes.

Zhaowei Jiang

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