The systematic separation strategy has long and widely been applied in the research and development of herbal medicines. However, the pharmacological effects of many bioactive constituents are much weaker than those of the corresponding herbal extracts. Thus, there is a consensus that purer herbal extracts are sometimes less effective. Pharmacological loss of purified constituents is closely associated with their significantly reduced intestinal absorption after oral administration. In this review, pharmacokinetic synergies among constituents in herbal extracts during intestinal absorption were systematically summarized to broaden the general understanding of the pharmaceutical nature of herbal medicines. Briefly, some coexisting constituents including plant-produced primary and secondary metabolites, promote the intestinal absorption of active constituents by improving solubility, inhibiting first-pass elimination mediated by drug-metabolizing enzymes or drug transporters, increasing the membrane permeability of enterocytes, and reversibly opening the paracellular tight junction between enterocytes. Moreover, some coexisting constituents change the forms of bioactive constituents via mechanisms including the formation of natural nanoparticles. This review will focus on explaining this new synergistic mechanism. Thus, herbal extracts can be considered mixtures of bioactive compounds and pharmacokinetic synergists. This review may provide ideas and strategies for further research and development of herbal medicines.

Background/Objectives: Natural macromolecule-based drug delivery carriers have gained extensive attention for biomedical applications. This study aimed to construct an efficient oral delivery system for the widely used antitumor drug docetaxel (DTX) by utilizing natural nanoparticles derived from Ganoderma (LZ-Nnps). Methods: LZ-Nnps loaded with DTX (LZ-Nnps-DTX) were fabricated via an optimized heat-induced self-assembly approach and characterized for morphology, particle size, zeta potential, stability, drug loading, encapsulation efficiency, and molecular interactions with DTX. Intestinal absorption, pharmacokinetics, and tissue distribution were respectively assessed, while antitumor efficacy, macrophage internalization mechanisms, and immunomodulatory activation were further investigated. Results: The optimized formulation showed a particle size of 361.3 ± 5.3 nm, zeta potential of −39.55 ± 1.31 mV, drug loading of 1.51 ± 0.08%, and near-complete encapsulation efficiency (99.97 ± 0.02%), with favorable stability in gastrointestinal fluids. Hydrogen bonding and hydrophobic interactions effectively kept DTX in a stable amorphous state. LZ-Nnps-DTX markedly improved DTX aqueous solubility, dissolution, and intestinal absorption. In vivo assays showed oral LZ-Nnps-DTX achieved 34-fold higher C_max and 7.8-fold larger plasma AUC_0-t than free DTX, and mainly accumulated in the liver and lung. The nanoparticles entered Caco-2 cells via macropinocytosis and mainly accumulated in the liver. LZ-Nnps-DTX exerted strong cytotoxicity against HepG2, A549, and HCT116 cells, was internalized by RAW264.7 macrophages through caveolae-mediated endocytosis and phagocytosis, and stimulated TNF-α and NO production to suppress tumor growth. Conclusions: These findings demonstrate that LZ-Nnps-DTX effectively enhances oral bioavailability, exerts potent antitumor effects, and activates macrophage-mediated immunity, supporting its promise as an oral DTX delivery system.