Trotline-Inspired Mesoporous Carriers for Prolonged Gastrointestinal Retention.

Overcoming the challenges of precise localization, prolonged retention, and targeted release remains a fundamental barrier in the development of effective oral drug delivery systems. These limitations are particularly critical in diseases requiring site-specific action within the gastrointestinal (GI) tract such as inflammatory bowel disease (IBD). Inspired by the trotline fishing technique, where multiple hooks are suspended along a main line to increase capture efficiency, we present a smart oral drug delivery platform featuring trotline-inspired mesoporous carriers with dynamic anchoring capability. This delivery system integrates three key components: (1) a trotline-inspired bioadhesive carrier, consisting of carbon nanotube (CNT) decorated with multiple submicrometer-scale periodic mesoporous organosilica (PMO) "hooks" (denoted as CNT@PMOs or CNTP); (2) therapeutic drugs loaded within the PMO mesopores (such as 5-aminosalicylic acid (5-ASA) for IBD); (3) a reactive oxygen species (ROS)-responsive camouflage polymer coating, designed to modulate site-specific adhesion and on-demand drug release. Following oral administration, the outer polymer coating effectively shields the PMO hooks, facilitating safe passage through the stomach and healthy intestinal regions. Upon reaching inflamed sites in the intestine, the elevated ROS levels trigger the degradation of the polymer coating, exposing the PMO hooks. This controlled unmasking enables selective adhesion to inflamed tissues and prolongs local drug retention. Simultaneously, degradation of the polymer also triggers controlled release of 5-ASA at the lesion site. The one-dimensional, multihooked design further enhances mechanical interlocking with the intestinal mucosa, anchoring the carrier at the desired site. Importantly, the system shows minimal systemic exposure, with nearly 100% fecal excretion of unabsorbed carriers within 72 h. By integrating stimuli-responsive activation, dynamic anchoring, and spatiotemporal drug release, this platform addresses long-standing barriers in oral drug delivery. It offers a broadly applicable strategy for enhancing therapeutic precision and efficacy in GI-targeted treatments and beyond.