Anisotropic excipient-free buccal wafer engineered by directional freezing for structure-guided neuro-immune therapy...

The management of chemotherapy-induced nausea and vomiting (CINV) in dysphagic patients is limited by the absence of mucosal delivery platforms that combine ultrafast adhesion, sustained release, and excipient-free composition. To address this, we engineered an excipient-free, anisotropic buccal wafer (IJ-ODW) via directional freeze-drying. The material features an engineered bilayered architecture, a dense top stratum integrated with a lamellar porous substrate, which resolves the mucosal "speed-stability paradox" by enabling ultrafast disintegration (15 s) together with strong, hydrogen-bond-mediated mucoadhesion (1.80 ± 0.44 gf). This structured wafer further exhibits polarity-selective permeability, facilitating the diffusion of lipophilic payloads while retaining polar phenolics for spatiotemporally controlled release. In a cisplatin-induced rat emesis model, IJ-ODW reduced kaolin intake by 18.3% (p < 0.01) and outperformed standard ondansetron-dexamethasone therapy, particularly during the delayed phase (36-120 h). Pharmacokinetic analysis confirmed effective first-pass bypass, with a 1.5-fold increase in AUC_0-24 and rapid absorption (T_max = 0.19 h), alongside structure-driven sustained exposure to chlorogenic acid (> 10 h). Mechanistically, the material operates through a biphasic neuro-immune regulatory cascade: rapid peripheral blockade of 5-HT₃/NK₁ receptors (40.7% reduction in serum 5-HT) followed by sustained immunomodulation via suppression of IL-6 signaling (46.0% decrease) and macrophage M2 polarization. Transcriptomic and network pharmacology analyses validated coordinated downregulation of emetic neurocircuitry (TPH1, Drd1, Drd2) and inflammatory hub genes (IL-6, TNF, NF-κB), establishing gut-brain axis reprogramming. The excipient-free composition ensures enhanced biocompatibility and pilot-scale reproducibility, delivering superior stability and antiemetic efficacy compared to a commercial ondansetron film. This work demonstrates how rational anisotropic structuring can transform a biopolymer into a multifunctional, therapeutic biomaterial platform that simultaneously addresses critical formulation barriers and complex pathophysiology, offering a scalable and dysphagia-tailored strategy for precision antiemesis. STATEMENT OF SIGNIFICANCE: This study reports the rational design of an anisotropic, excipient-free buccal wafer, which overcomes the fundamental "speed-stability paradox" in mucosal delivery through its engineered bilayered architecture. By integrating ultrafast adhesion with sustained, polarity-selective release and active neuro-immune modulation, this material platform provides a scalable and dysphagia-tailored therapeutic strategy, advancing the design of multifunctional biomaterials for complex clinical needs.