Ultrasound-guided, magnetothermal wax capsule for localized gastrointestinal drug delivery

Oral drug delivery to specific lesions in the gastrointestinal (GI) tract remains a major challenge. The current systems depend on internal physiological triggers such as pH, enzymatic activity, and luminal pressure, which exhibit wide intra- and inter-patient variability. 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), with ultrasound imaging used for real-time localization. The capsule is composed of a low-melting-point wax matrix embedded with superparamagnetic iron oxide nanoparticles (SPIONs), which generate heat upon AMF exposure, resulting in rapid wax melting and burst drug release. SPIONs exhibited no toxicity in zebrafish embryonic development, demonstrating excellent biocompatibility. Capsules were fabricated in a hemispherical shape using a 3D-printed mold, yielding highly reproducible batches with a mass variation within ±10%. A Design of Experiments (DoE) approach identified an optimized formulation comprising a 6:4 docosane:eicosane wax blend, 10 wt% SPION loading, and a 1.5 mm capsule shell thickness, achieving efficient magnetic heating while maintaining mechanical strength (> 2 N), sufficient for withstanding GI transit. The optimized capsule formulation exhibited no cytotoxicity in vitro and remained intact throughout sequential incubation in simulated gastric, intestinal, and colonic fluids. No drug leakage or significant metal leaching (≤ 0.6%) was obtained. The capsule was successfully visualized in a porcine abdominal model using a handheld ultrasound device commonly used at the bedside in the clinic. AMF exposure triggered complete drug release within 33 seconds in vitro. In vivo studies in mice further demonstrated capsule localization via ultrasound, and AMF-triggered capsule melting in the colon via endoscopy. In conclusion, this magnetothermal capsule platform integrates non-invasive imaging and externally triggered drug release to enable localized GI drug delivery, representing a promising strategy for precision treatment of GI diseases.