Hydrogen-Bonded Organic Frameworks for Biomedical Application: Smart Diagnosis, Precision Delivery and Synergistic Therapy.
Reticular chemistry has enabled the design of crystalline porous frameworks, including metal-organic frameworks (MOFs) and covalent organic frameworks (COFs), with exceptional structural precision and functionality. Among these, hydrogen‑bonded organic frameworks (HOFs) represent a uniquely biocompatible class, constructed through reversible hydrogen bonds that confer dynamic responsiveness, mild‑condition processability, and inherent metal‑free composition. Despite these advantages ideal for biomedical use, HOFs remain underexplored in medicine compared to their coordination and covalent counterparts. This review systematically charts the emergence of HOFs as a versatile platform for biomedical applications. We first outline he design principles, synthetic strategies, and key parameters that govern the biomedical applications of HOFs. The core of the review focuses on the current state-of-the-art applications in biomarker detection, diagnostic imaging, advanced drug delivery, and therapeutic interventions. We discuss how the reversible and stimuli-responsive characteristics of HOFs enable intelligent functions and applications, such as multi-functional integration, triggered drug release and combination therapies. Finally, this review identifies the remaining challenges facing the field, while offering forward-looking perspectives on the clinical translation and future innovations of HOF-based nanomedicines. STATEMENT OF SIGNIFICANCE: Hydrogen-bonded organic frameworks (HOFs) are an emerging class of crystalline porous materials that combine metal-free composition, intrinsic biocompatibility, structural tunability, and stimuli-responsive hydrogen-bonded networks. Despite their rapid development in gas storage, separation, and catalysis, their biomedical potential remains largely unexplored. In this review, we summarize recent progress in the design and synthesis of HOFs and their applications in disease diagnosis, drug delivery, and therapeutic interventions. We further discuss the underlying mechanisms governing their biomedical functions and highlight key challenges that limit their translational development. Finally, we outline future research directions toward advancing HOFs for biomedical applications at the interface of supramolecular chemistry, materials science, and nanomedicine.