Self-assembled structures as a material basis for indirect pharmacology in Traditional Chinese Medicine

Indirect pharmacology is increasingly invoked to explain how Traditional Chinese Medicine (TCM) and natural products produce therapeutic effects through inter-organ communication and distributed physiological regulation rather than through direct action on a single molecular target. In this context, most mechanistic discussions emphasize downstream mediators, including microbial metabolites, immune signals, and endocrine factors, but pay less attention to the material form in which complex preparations are administered. This review examines the possibility that self-assembled structures in decoctions constitute an underappreciated upstream determinant of indirect pharmacology. Decoctions are not simply molecular solutions; during preparation and after exposure to biological environments, they can form colloids, aggregates, and multicomponent co-assemblies. These material states may influence intestinal localization, mucosal retention, microbial access, barrier interactions, and the spatial pattern of mediator generation. We synthesize evidence from two related lines of research: naturally occurring aggregates in traditional decoctions and bottom-up assemblies constructed from isolated phytochemicals. Across representative case studies, current evidence supports a role for supramolecular organization in shaping exposure and interface-level behavior, but direct causal links to defined mediator chains and distal organ outcomes remain limited. We therefore outline methodological strategies for testing structure-interface-mediator relationships more rigorously in future studies.