# Dual-Stimuli Responsive Antibiotic-Loaded Nanoparticles: A New Strategy to Overcome Antimicrobial Resistance

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $486,236

## Abstract

PROJECT SUMMARY
Infectious diseases are a growing threat to public health owing to increasing antimicrobial resistance (AMR) and
stagnation in new antibiotic development. Left unchecked, the annual number of deaths attributable to AMR is
estimated to reach 10 million by 2050, exceeding deaths due to cancers and diabetes. Thus, there is an urgent
need to develop innovative approaches to tackle this serious global crisis. We aim to develop a new class of
dual-stimuli responsive polysaccharide-coated nanoparticles (NP) capable of encapsulating a wide range of
FDA-approved antibiotics to effectively treat multidrug-resistant (MDR) bacterial infections. The polysaccharide
NP shell ensures good stability and long blood circulation time, thus leading to high NP accumulation in the
infected tissues via the enhanced permeation and retention effect. Furthermore, polysaccharides enable the NP
to physically bind the pathogens due to multivalent affinity for bacterial lectins. The uniquely engineered NP is
activated by high levels of ROS and/or low pH in the inflammatory microenvironment to release both cationic
antimicrobial polymers and antibiotics that show a strong synergy to combat MDR pathogens. The cationic
polymers can induce pores on the bacterial cell membrane, and significantly diminish the intrinsic resistance of
the pathogens by enhancing the transport of antibiotics into the bacteria and allowing them to bypass the efflux
pump. The cationic polymers released in the infected tissues can also agglomerate the pathogens and shape a
microenvironment entrapping a high level of antimicrobial materials, thus leading to high antimicrobial efficacy.
Moreover, the NP can penetrate through bacterial biofilms, and enhance the uptake of antibiotics by macro-
phages, thereby effectively eliminating notoriously challenging biofilm and intracellular infections, respectively.
Finally, the cationic polymer contains GSH-cleavable bonds in its main chain, which can be readily degraded in
the cytosol of mammalian cells, thereby sidestepping the problem of dose-limiting toxicity with other cationic
polymers. Following on our successful pilot studies, we will systematically optimize and characterize NPs tailored
to treat four different MDR pathogens. In Aim 1, we will determine the optimal polysaccharide NP shell, antibiotics,
and NP formulation for each of the four MDR pathogens. In Aim 2, we will study the candidate NPs’ antimicrobial
and antibiofilm efficacy, drug resistance development profile, and biocompatibility to gain a fundamental
understanding of the design rules for efficacious and safe antimicrobial NP against pathogens of interest. In Aim
3, we will determine the maximum tolerated dose, systemic toxicity, immunological consequences, in vivo
biodistribution, pharmacokinetics, and antimicrobial efficacy of the selected NPs in healthy mice and three
clinically relevant animal infection models. Altogether, this study will lead to a new class of antimicrobial ...

## Key facts

- **NIH application ID:** 10862787
- **Project number:** 5R01AI177173-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SHAOQIN - GONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $486,236
- **Award type:** 5
- **Project period:** 2023-06-08 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862787

## Citation

> US National Institutes of Health, RePORTER application 10862787, Dual-Stimuli Responsive Antibiotic-Loaded Nanoparticles: A New Strategy to Overcome Antimicrobial Resistance (5R01AI177173-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10862787. Licensed CC0.

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