Noncovalent And Host–guest Supramolecular Complexes in Nanomedicine: Self-healing Materials, Biomaterial Hydrogels, Bioimaging and Regenerative Medicine

Abstract

Supramolecular complexes assembled through noncovalent and host–guest interactions have become a central design strategy in nanomedicine, offering reversibility, stimuli-responsiveness and dynamic structural adaptation that covalent constructs cannot easily reproduce. This critical narrative review examines how four application areas, namely self-healing materials, injectable biomaterial hydrogels, bioimaging and regenerative medicine, have been shaped by a shared molecular toolkit comprising cyclodextrins, cucurbit[n]urils, pillar[n]arenes, calixarenes, hydrogen-bonded ureidopyrimidinone units and peptide assemblies. The analysis distinguishes well-supported conclusions from claims that remain preliminary. The quantitative relationship between host–guest binding thermodynamics, cross-link exchange kinetics and macroscopic material behaviour is now established across several independent platforms, and the capacity of dynamic networks to support injectability, cell infiltration and mechanotransduction is reproducibly demonstrated in vitro and in small-animal models. Translation diverges sharply across domains. Macrocyclic solubilising excipients and a cyclodextrin-based neuromuscular reversal agent have reached routine clinical use, and self-assembling peptide gels have entered controlled clinical testing for enamel remineralisation and endoscopic haemostasis, yet the self-healing, imaging and regenerative constructs that most fully exploit host–guest recognition remain almost entirely preclinical. Recurring weaknesses include heterogeneous and non-standardised reporting of self-healing efficiency, small and short-duration animal studies, uneven characterisation of in vivo complex stability, and persistent gaps in long-term immunological and clearance data for synthetic macrocycles. Pretargeted nuclear imaging using cucurbituril–adamantane pairs and xenon biosensors illustrates both the precision achievable and the distance still separating mechanistic elegance from clinical readiness. The evidence supports a measured conclusion: noncovalent supramolecular design is a mature conceptual framework with selective, not general, translational maturity. Progress now depends less on new host–guest chemistries than on standardised characterisation, larger and longer in vivo studies, and sustained attention to immunogenicity, degradation and reproducible manufacturing.