Purpose <p>Oral liposomal drug delivery systems have been developed to enhance the bioavailability of poorly water-soluble drugs. However, their clinical application is often limited by poor stability in the gastrointestinal tract and during storage. Although proliposomes offer improved stability in solid-state form, conventional formulations tend to rapidly generate liposomes in the stomach in an uncontrolled manner, thereby potentially compromising drug stability and absorption. To address these limitations, we developed a novel oral liposomal formulation using a water-insoluble bentonite (BT) matrix to enable selective liposome release in the intestine.</p> Methods <p>Apatinib (APT), a poorly water-soluble model drug, was encapsulated in liposomes containing phosphatidylcholine. These liposomes were adsorbed onto BT via electrostatic interactions to form the apatinib-loaded liposome-bentonite composite (ALBC). The pH-dependent surface charge shift altered the ionic interactions between the liposomes and BT, enabling controlled liposome release in the intestine.</p> Results <p>Transmission electron microscopy and dynamic light scattering analyses demonstrated that liposomes were generated and released from the ALBC in a pH-dependent manner. In vitro release studies revealed minimal liposome release under acidic conditions and enhanced liposome formation and release at intestinal pH. In vivo pharmacokinetic studies showed that ALBC significantly improved oral bioavailability of APT while delaying its time-to-maximum plasma concentration.</p> Conclusion <p>These findings suggest that BT could be a promising matrix for developing intestinally targeted liposomal formulations capable of overcoming the inherent limitations of conventional oral liposomal delivery systems.</p>