Combination chemotherapy is a cornerstone of non-small cell lung cancer (NSCLC) treatment, with cisplatin (CDDP) serving as a frontline agent, but its clinical utility is severely compromised by resistance and systemic toxicity. Overcoming these limitations requires both effective CDDP-sensitizing agents and delivery systems capable of precisely controlling drug ratios and release sequence. Here, we identified Icariside II (IS), a bioactive flavonoid from Epimedium species, as a potent CDDP sensitizer. Synergy analyses confirmed that IS and CDDP exert strong cooperative effects at a 1:2 molar ratio. Mechanistically, IS downregulated HMGCR/SREBF2, reduced intracellular cholesterol, and enhanced CDDP uptake and DNA damage, with IS pretreatment followed by CDDP producing the strongest antitumor effects. Guided by this mechanism, we engineered dual-drug polymer–lipid hybrid nanoparticles using a custom TrH microfluidic chip. Distinct from conventional methods, the TrH platform enabled programmable co-encapsulation with precise ratio control and intrinsic, stimulus-independent sequential release. Among the formulations, CDDP-IS@MNPs—programmed to release IS prior to CDDP—most effectively recapitulated the optimal sequence, inducing robust apoptosis in vitro, >70% tumor growth inhibition in xenografts, prolonged survival in orthotopic models, and reduced cisplatin-induced hepatic and renal toxicity. Collectively, compared with our previous formulation-oriented work, this study achieves a substantial conceptual advance by integrating mechanistic insight with programmable microfluidic design, transforming the TrH chip into a preclinically validated platform for stepwise nanomedicine delivery, while also providing a promising therapeutic strategy to address the long-standing challenges of cisplatin-based combination chemotherapy.

Astragalus is a functional plant with notable medicinal and nutraceutical value, and its combination with honey represents a classic pairing in traditional dietary therapy. To address the low oral bioavailability of Astragalus flavonoids (AFs, including calycosin-7-O-β-D-glucoside, ononin, calycosin, and formononetin), the primary bioactive components of Astragalus, our study demonstrated that honey significantly increases the systemic exposure of AFs, thereby enhancing oral bioavailability. These enhancement effects are attributed to the supramolecular structures in honey that interact with AFs through intermolecular non-covalent interactions, and reversible modulation of tight junction barriers by honey, which facilitates the paracellular absorption of AFs. Furthermore, honey’s absorption-enhancing effects were validated by the enhanced Qi-tonifying (enhancement of the body’s vital energy to defend illnesses) efficacy observed in the AFs-honey combination. Our findings provide scientific references for the potential application of honey as a natural absorption enhancer, while offering novel insights into the traditional combination of Astragalus and honey.