Nano-microbiome interactions in human health and disease exploring therapeutic opportunities, toxicological risks and future directions

Nanotechnology is rapidly advancing in biomedical, pharmaceutical, environmental and consumer applications, leading to increasing exposure of humans to engineered nanomaterials (ENMs) with a corresponding growing interest in their interactions with the human microbiome. The microbiome, often referred to as the “hidden organ” and plays a critical role in immune regulation, metabolism, tissue homeostasis, and disease processes. Experimental and preclinical studies suggest that nano-sized particles can directly and indirectly affect microbial ecosystems by mechanisms such as generation of reactive oxygen species, disruption of microbial membranes, quorum sensing disruption, and modulation of microbial signaling pathways. These interactions have therapeutic implications as well as potential toxicological implications. Nanomaterials have shown promise in pre-clinical studies for multiple applications such as antimicrobial therapy, disruption of biofilms, modulation of the microbiome, smart wound healing, and precision medicine, particularly by combining hydrogels, probiotics, and stimuli-responsive systems in microbiome-responsive nanoplatforms. However, emerging evidence indicates that long-term exposure to nanoparticles may contribute to dysbiosis, chronic inflammation, the emergence of antimicrobial resistance, immune system dysfunction and ecosystem disruption, although the clinical significance of these effects in humans remains limited. This review provides a comprehensive overview of nano-microbiome interactions, therapeutic applications, toxicological risks, novel advancements in organoid models, multi-omics technologies, artificial intelligence-based prediction, and personalized nanomedicine based on the microbiome for future clinically relevant therapeutic strategies, while highlighting existing knowledge gaps and future research areas that would be useful for clinical translation.