Rethinking Nanoparticle Therapeutics: Phytochemical Self-aggregation as a Hidden Driver of Biological Performance

Abstract

Natural products remain a cornerstone of drug discovery, providing structurally diverse bioactive compounds with significant therapeutic potential. Their incorporation into nanomedicine, either as active pharmaceutical ingredients or functional excipients, has expanded rapidly due to their ability to improve solubility, bioavailability, and targeted delivery. However, a fundamental assumption persists in current research: phytochemicals are typically treated as discrete, chemically uniform, and molecularly dispersed prior to nanoparticle formulation. This reductionist view overlooks the inherent complexity of natural extracts, which exist as multicomponent and dynamically interacting systems. In this work, we propose a hypothesis that challenges this assumption by introducing the concept of pre-nanoparticle molecular organization (PNMO). We suggest that phytochemicals in crude or semi-purified extracts undergo intrinsic self-aggregation and supramolecular assembly before nanoparticle fabrication. These assemblies are governed by non-covalent interactions, including hydrogen bonding, π–π stacking, hydrophobic forces, and electrostatic interactions, resulting in pre-formed molecular clusters. We argue that PNMO critically influences key nanoparticle characteristics such as size distribution, morphology, colloidal stability, and drug loading efficiency, as well as downstream biological performance. Neglecting this pre-formulation state may lead to inconsistencies in physicochemical characterization, poor reproducibility, and challenges in quality control. Moreover, PNMO may alter biodistribution, cellular uptake, and therapeutic outcomes, complicating structure–activity relationship analyses. By integrating principles from supramolecular chemistry and nanomedicine, this review highlights PNMO as an essential yet overlooked design parameter. Its systematic characterization and control may enable more reproducible formulations and facilitate the rational development and clinical translation of phytochemical-based nanotherapeutics.