The next paradigm in bioinformatics: a review of multi-agent systems and foundational models for end-to-end...

Bioinformatics is entering a new phase characterized by the integration of universal biological models and multi-agent systems to enable end-to-end scientific discoveries. This review argues that the next paradigm shift will go beyond traditional predictive models and generative artificial intelligence (AI) toward agentic AI: systems capable of planning, acting through tools, reflecting on results, and iterating until a goal is achieved. We first examine recent foundational models that produce transferable representations across omic modalities, such as scGPT, Nicheformer, and EpiAgent, and discuss their architectural choices, training regimes, and interpretability constraints. We then analyze biomedical agent frameworks through their main components (planning, action, reflection, and memory), highlighting representative systems such as ClinicalAgent and Biomni that operationalize these ideas in controlled environments. Next, we focus on hypothesis validation mechanisms, including retrieval-augmented generation for evidence grounding, sequential statistical testing, and benchmarking methodologies designed to quantify robustness and reproducibility. Finally, we summarize emerging applications in drug discovery and personalized medicine, from molecular literature analysis and protocol automation to drug repurposing for rare diseases and closed-loop synthesis. We conclude by outlining the main challenges ahead, namely hallucinations, interpretability, systemic biases, integration with clinical infrastructures, and regulatory and ethical requirements, and propose a roadmap for the development of scientific agents that are not only high-performing but also reliable, verifiable, and implementable in real biomedical contexts.