Dual-Mechanism Aptamer–Drug Complex Overcomes Paclitaxel Resistance in Ovarian Cancer via Structural Constraint and Telomerase Inhibition

Paclitaxel resistance and poor tumor selectivity remain significant challenges in epithelial ovarian cancer therapy. To overcome these challenges, we engineered PSaA360, a structurally constrained aptamer-drug conjugate with a dual-functional molecular lock that simultaneously rigidifies the AS1411 aptamer and delivers potent telomerase inhibition. Unlike the conformational flexibility of conventional aptamer-drug conjugates, PSaA360 employs the G-quadruplex stabilizer 360A to simultaneously rigidify the AS1411 aptamer into a high-affinity conformation and deliver potent telomerase inhibition. This structure-constrained and therapy-integrated strategy improved nucleolin binding, enhanced cellular internalization, and counteracted paclitaxel chemoresistance. In vivo, PSaA360 exhibited marked tumor inhibition with minimal systemic toxicity. By transforming a therapeutic agent into a structural stabilizer, PSaA360 establishes a new paradigm for mechanism-guided aptamer engineering in chemotherapy-resistant malignancies.