Nab-paclitaxel fused with the de novo designed receptor binder exhibits enhanced tumor targeting and therapeutic efficacy

Chemotherapy has been widely used in cancer treatment, but most of the chemotherapeutic drugs rely mainly on passive accumulation due to lack of target specificity, which may lead to systemic toxicity and limited clinical utility. Recent advances in artificial intelligence-based protein design provide new opportunities for developing precision therapeutics. Here we modify the albumin-bound paclitaxel (Nab-PTX), one of the most widely used drugs in chemotherapies, by applying the fusion proteins of albumin with the de novo designed protein binders targeting human EGFR or HER2. The resulting particles, EGFRmb-Nab-PTX and HER2mb-Nab-PTX, retain the similar physicochemical properties of Nab-PTX while acquiring the receptor-specific binding capacities. The in vitro assays show that both binder-modified Nab-PTX particles have increased uptake and inhibitory effects significantly in the cancer cell lines with high receptor expression levels. Furthermore, the data from a xenograft model, including tumor growth, excised tumor analysis, organ histology, and fluorescence imaging, show that the binder-modified Nab-PTX enhances tumor accumulation, improves tumor suppression, and reduces off-target toxicity compared with the conventional Nab-PTX, suggesting that they may have promising clinical potential in cancer treatment. Overall, this strategy provides an adaptable modular platform for generating albumin-based chemotherapeutic drugs with target specificities, which can be readily customized with diverse target binders to enable precise cancer therapies.