Targeted Therapeutic Efficacy of Three-Layer Core–Shell VPPS Composite Nanogel Against Proliferative Enteropathy Induced by Lawsonia intracellularis

The obligate intracellular parasitic nature of Lawsonia intracellularis (L. intracellularis) enables it to evade host immune clearance and conventional antimicrobial action, leading to considerable therapeutic challenges and high recurrence rates. Current strategies, including vaccination and conventional antibiotic therapy, remain constrained by incomplete protection and insufficient intracellular drug delivery, underscoring the urgent need for novel oral targeted delivery strategies. Thus, the valnemulin-derived carbon dots were prepared via a hydrothermal method and sequentially encapsulated with poloxamer, high-methoxyl pectin, and sucrose to assemble a three-layer core–shell VPP NPs to address these limitations. The VPPS NPs was optimized using response surface methodology and systematically evaluated the resulting system for physicochemical properties, pH and pectinase dual-responsive release behavior, targeted antibacterial efficacy, and in vivo therapeutic performance and biosafety. Physicochemical characterization showed that VPPS NPs had a typical core–shell structure and a three-dimensional porous network with a final particle size of 122.9 ± 8.7 nm, and Fourier transform infrared spectroscopy and X-ray diffraction confirmed successful assembly and intermolecular interactions among the components. In vitro release studies revealed pH/pectinase dual-responsive release behavior, characterized by partial acid resistance in simulated gastric fluid (11.4 ± 1.6% cumulative release at 2 h) and rapid release in the neutral intestinal environment (97.8 ± 2.0% at pH 7.4), with release significantly accelerated in the presence of pectinase (72.4 ± 1.7% vs. 32.8 ± 2.8% without pectinase). VPPS NPs were efficiently internalized by intestinal epithelial cells, resulting in substantially higher intracellular drug accumulation than free drug (25.2 ± 2.9 μg/mg protein vs. 0.03 ± 0.003 μg/mg protein), and could directly disrupt the cell wall and membrane structures of intracellular L. intracellularis. Furthermore, VPPS NPs achieved 100% survival and cure rates in infected mice, which are significantly higher than those of the commercial VH solution (70% and 50%, respectively), while restoring intestinal barrier function, alleviating oxidative stress, and modulating inflammatory responses. Biosafety evaluation confirmed the favorable biosafety profile of VPPS NPs. Collectively, VPPS NPs accomplished efficient targeted therapy against L. intracellularis infection through multi-level synergistic actions, offering an innovative strategy and technological platform for the oral treatment of proliferative enteropathy.