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.