Biofilm formation: Regulatory mechanisms and therapeutic strategies

Biofilm formation and development are dynamically regulated processes. The core regulation involves cell-to-cell communication mediated by quorum-sensing (QS) mechanisms and enhanced intrinsic resistance via efflux pumps. These mechanisms establish a robust barrier against antibiotics and host immune responses. In response, strategies for biofilm eradication have evolved from singular antimicrobial interventions to interdisciplinary synergistic approaches. Current research primarily focuses on synergistic combined therapies that integrate advanced nanoplatforms with physical field interventions. This review has refined an integrated intervention strategy of internal and external collaboration, using internal molecular targeting for precise localization and external physical fields for powerful disintegration, thereby achieving synergistic effects of physical structure destruction, signal pathway interference, and precise drug release. This review systematically summarizes the mechanisms of biofilm formation and regulation, integrates the bidirectional interactive regulatory network of QS and c-di-GMP, and clarifies the dual roles of efflux pumps in biofilms-direct resistance and indirect regulation. With a particular emphasis on the latest advancements, synergistic mechanisms, and prevailing challenges associated with multimodal eradication strategies, proposes a future research roadmap that progresses from omics and in situ imaging to the identification of new targets and ultimately to the development of intelligent responsive systems. It aims to provide a theoretical reference and insights for developing the next generation of efficient and precise therapies for biofilm-associated infections.