Hierarchically Dual-Targeted Casein-Coated Iron Oxide Nanoparticles as Oral Thermal Agents for Noninvasive and Reversible Male Contraception

Mild testicular hyperthermia holds promise as a contraceptive approach. However, the great challenge lies in developing well-tolerated and highly targeted methods for testicular hyperthermia. Here, we engineered dual-targeted casein (CN) coated magnetic iron oxide nanoparticles as oral thermal agents for male contraception. The core Fe₃O₄, facilitating magnetic targeting and magnetic hyperthermia, was conjugated with anti-luteinizing hormone receptor (anti-LHR) by initial H₂N-PEG-NH₂ modification and then coated with CN in a layer-by-layer fashion (MNs@LC). MNs@LC exhibited remarkable stability in the gastric environment after oral administration under magnetic guidance. Upon reaching the intestine, enzymatic cleavage of casein exposed the anti-LHR, enabling active targeting and increased cellular uptake. In vivo investigations validated the improved accumulation of the dual-targeted system in the testis, allowing for high heating efficiency under an alternating magnetic field and ultimately achieving noninvasive and reversible contraception. This approach offers a fresh perspective on creating dual-targeted platforms for oral delivery strategies.