Bio-Inspired Mucus-Penetrating Micro Motors For Enhanced Pulmonary Delivery Of Antifungal Agents

Abstract

Pulmonary fungal infections such as invasive aspergillosis pose a serious therapeutic challenge due to the difficulty of delivering antifungal drugs directly to infection sites in the lungs. Current systemic therapies often have limited lung penetration and significant side effects,

While inhaled formulations face barriers like the respiratory mucus layer and rapid clearance. Here we propose a novel drug delivery approach using bio-inspired mucus-penetrating micromotors to actively transport antifungal agents through airway mucus and deposit them at target sites in the lungs. These micromotors draw inspiration from motile microorganisms (e.g. algae and bacteria) to achieve self-propulsion and navigate the lung environment. We discuss the design of biodegradable, biocompatible microrobots (≈1–10 µm) loaded with antifungal drugs, incorporating features such as flagellar locomotion, enzymatic mucus degradation, and non-adhesive coatings to facilitate mucus penetration. In preclinical studies, biohybrid microrobots coated with drug-loaded nanoparticles have demonstrated homogeneous lung distribution, prolonged retention (>5 days), avoidance of phagocytic clearance, and markedly improved therapeutic outcomes in pneumonia models. For example, algae-based microrobots loaded with antibiotics eradicated >99.9% of bacterial burden in infected mouse lungs and achieved 100% survival, outperforming free drug therapy. Catalase-powered nanomotors have shown a 60-fold increase in mucus penetration compared to passive particles. We envision that such active, bio-inspired delivery systems can revolutionize pulmonary antifungal therapy by enhancing drug localization in the lungs while minimizing systemic exposure. This article reviews the pulmonary mucus barrier, the design and fabrication of bio-inspired micromotors, and evidence of their efficacy in improving lung drug delivery. Twenty relevant references are cited in support of this emerging interdisciplinary approach. The findings highlight the potential of mucus-penetrating microrobots to significantly improve treatment of respiratory fungal infections through targeted, efficient pulmonary drug delivery.