Quaternary ammonium compound-based ionic liquid with microwave responsiveness for treating deep tissue infections without compromising biocompatibility

Abstract

Quaternary ammonium compounds (QACs) hold great promise as alternatives to conventional antibiotics due to their broad-spectrum antibacterial activity and minimal propensity for inducing bacterial drug resistance. However, their inherent cytotoxicity and pro-inflammatory property perpetuate an intractable efficacy-biocompatibility trade-off, severely limiting clinical translation. Herein, aimed to solve this dilemma, we developed a microwave-responsive ionic liquid (IL) via the integration of QACs with an anti-inflammatory anionic organic compound, enabling synergistic bactericidal efficacy through microwave-induced hyperthermia while concomitantly alleviating QAC-related toxicity and inflammation. After loading into bacteria-targeted hollow polydopamine nanoparticles (HPDA NPs), this IL-based nanoplatform exhibited selective biocidal discrimination between bacterial and mammalian cells, fundamentally mitigating QAC-related cytotoxicity. Notably, embedding these nanoparticles into poly (vinyl pyrrolidone) MNs (IL@HPDA@MN) achieved up to 99.8% bactericidal efficiency coupled with robust anti-inflammatory effects in a mouse subcutaneous abscess model, leading to accelerated abscess resolution and tissue regeneration that outperformed clinical antibiotics. Beyond resolving the QAC-centric efficacy-biocompatibility paradox, this work provides a generalizable framework for engineering toxic cationic antibacterial agents into biocompatible, targeted therapeutics, offering a transformative approach for treating deep-seated bacterial infections that are refractory to traditional therapies.

Statement of significance

Quaternary ammonium compounds (QACs) are promising alternatives to conventional antibiotics due to their broad-spectrum activity and low resistance risk. Yet, their clinical adoption remains paralyzed by an inherent trade-off between bactericidal efficacy and unacceptable cytotoxicity, pro-inflammation. Here, we break this deadlock by rationally integrating a QAC with an anti‑inflammatory organic compound to form a microwave-responsive ionic liquid (IL). When encapsulated in bacteria-targeted hollow polydopamine nanoparticles and further loaded into a dissolvable microneedle patch, this IL-based platform achieves potent bacterial killing under mild microwave irradiation while exhibiting negligible toxicity toward mammalian cells. In a murine subcutaneous abscess model, the system rapidly resolves deep-seated infections and curtails local inflammation, achieving therapeutic outcomes that rival or surpass those of clinical antibiotics. Beyond offering a ready-to-use strategy for treating refractory deep-tissue infections, this work establishes a generalizable paradigm for converting toxic cationic antimicrobials into biocompatible, spatially controllable therapeutics.