Plant cells represent smart cargo carriers with great socioeconomic potential in oral drug delivery applications. The two exterior barriers, featuring a rigid cell wall and a dense plasma membrane, are unique with complementary structural, mechanical, and chemical properties. Current strategies for producing therapeutic drugs within plant cells for oral delivery are efficient, but largely limited to recombinant pharmaceutical proteins, and involve complex genetic modification of plants. To address this, we engineer plant cell–inspired delivery systems with cellulose nanofiber–based shells and lipid layers through a bottom-up assembly strategy, which offers greater flexibility to encapsulate nonprotein compounds and nanoparticles. Notably, the layered shell structure resists degradation in acidic environments, and two barriers respond differently to external stimuli in simulated gastrointestinal medium, resulting in size-dependent dual-triggered release mechanisms. The cytocompatibility was shown by incubation with Caco-2 cells. Our results open avenues for developing next generation of bioinspired oral delivery systems for multisite-specific gastrointestinal release in a low-cost and sustainable manner.