Magnetothermal Wax Capsule for Localized Gastrointestinal Drug Delivery

Abstract Oral drug delivery to gastrointestinal (GI) lesions remains challenging, as current systems rely on physiological triggers such as pH, enzymes, and luminal pressure, which vary widely among patients. To address this, an ingestible capsule was developed to enable on-demand, site-specific drug release in response to an external alternating magnetic field (AMF). The capsule comprises a low-melting-point wax matrix embedded with superparamagnetic iron oxide nanoparticles (SPIONs). Under AMF exposure, SPIONs generate heat, inducing rapid wax melting and burst drug release. Capsules were fabricated using 3D-printed molds, yielding reproducible batches. A Design of Experiments approach identified an optimal formulation that balanced heating efficiency with mechanical strength (>2 N), sufficient for GI transit. Optimized capsules showed no cytotoxicity in vitro, remained intact in simulated GI fluids, and exhibited no drug leakage and negligible metal leaching. AMF exposure triggered complete drug release within 33 s in vitro. Proof-of-concept in vivo capsule melting was also successfully demonstrated. However, localized heat-induced mucosal damage was observed in the mouse colon, highlighting the need to optimize the AMF operating conditions to establish a safe thermal operating window. For capsule localization, successful ultrasound imaging of the capsule was demonstrated in both an ex vivo porcine abdominal model and an in vivo mouse model. In conclusion, this magnetothermal capsule enables externally triggered drug release for localized GI drug delivery, representing a promising strategy for precision GI therapy.