Nano-bio interactions: A major principle in the dynamic biological processes of nano-assemblies

Controllable nano-assembly with stimuli-responsive groups is emerging as a powerful strategy to generate theranostic nanosystems that meet unique requirements in modern medicine. However, this prospective field is still in a proof-of-concept stage due to the gaps in our understanding of complex-(nano-assemblies)-complex-(biosystems) interactions. Indeed, stimuli-responsive assembly-disassembly is, in and of itself, a process of nano-bio interactions, the key steps for biological fate and functional activity of nano-assemblies. To provide a comprehensive understanding of these interactions in this review, we first propose a 4W1H principle (Where, When, What, Which and How) to delineate the relevant dynamic biological processes, behaviour and fate of nano-assemblies. We further summarize several key parameters that govern effective nano-bio interactions. The effects of these kinetic parameters on ADMET processes (absorption, distribution, metabolism, excretion and transformation) are then discussed. Furthermore, we provide an overview of the challenges facing the evaluation of nano-bio interactions of assembled nanodrugs. We finally conclude with future perspectives on safe-by-design and application-driven-design of nano-assemblies. This review will highlight the dynamic biological and physicochemical parameters of nano-bio interactions and bridge discrete concepts to build a full spectrum understanding of the biological outcomes of nano-assemblies. These principles are expected to pave the way for future development and clinical translation of precise, safe and effective nanomedicines with intelligent theranostic features.