Nanobody-Conjugated Theranostic Prodrug Targeting α<sub>v</sub>β<sub>3</sub> Integrin Enables Precision Cancer Therapy With Real-Time Imaging.

Karan, Sanu; Lee, Hyunseung; Naskar, Rema; Cho, Mi Young; Park, Hye Sun; Han, Eun Hee; Hore, Soumyadip; Cho, Sun Hee et al. · Adv Healthc Mater · 2026

basic_science · Level V

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Abstract

Theranostic prodrugs that integrate diagnostic and therapeutic functionalities represent a promising avenue for precision oncology. In this study, we report the rational design, synthesis, and preclinical evaluation of a nanobody-based α<sub>v</sub>β<sub>3</sub> integrin-targeted theranostic prodrug (NBD). The system incorporates a glutathione-responsive disulfide linker to enable selective release of doxorubicin within the tumor microenvironment, alongside an aza-BODIPY near-infrared fluorophore that providesactivatable imaging capability. Compared to its cRGD peptide-conjugated counterpart (cRBD), NBD demonstrated superior tumor selectivity, intracellular activation, and cytotoxic potency in α<sub>v</sub>β<sub>3</sub>-overexpressing cancer cell lines. In vivo studies using SKOV3 xenograft models confirmed prolonged tumor retention, enhanced drug accumulation, and potent tumor suppression, with minimal systemic toxicity. Moreover, real-time imaging enabled precise monitoring of prodrug activation and distribution. These findings highlight the unique advantages of nanobody-guided theranostic platforms in enabling targeted drug delivery, reducing off-target effects, and facilitating image-guided therapy. The modular design of NBD provides a versatile framework for advancing personalized cancer treatment strategies.