Abstract

Ricin is classified as a Category B biothreat agent due to its high toxicity and wide availability, posing a substantial threat to public security. Currently, no effective antidotes have been approved, and the development of medical countermeasures—including small-molecule inhibitors, antibodies, and vaccines—face substantial challenges. In this study, we designed innovative ricin-degrading antidotes based on the aptamer-autophagosome-tethering compound (aptamer-ATTEC) strategy. A series of aptamer-ATTEC chimeras were constructed by conjugating a high-affinity ricin aptamer with an LC3-recruiting moiety via click chemistry. The optimal compound, designated DP3-D-B0, exhibited potent anti-ricin efficacy at molecular, cellular, and animal levels. Experimental results confirmed that DP3-D-B0 mediated the formation of an intracellular ternary complex (LC3-ATTEC-ricin) that hijacks the autophagy machinery for lysosome-mediated degradation. Moreover, DP3-D-B0 was found can partially blocks ricin uptake extracellularly when administered simultaneously. This work broadens the application scope of ATTEC technology and provides a novel strategy for the targeted degradation of exogenous toxins, thus advancing the development of therapeutics against biothreat agents.