A genetically programmable, conjugation-free nanomedicine platform for modular antibody-guided drug delivery

Antibody-decorated nanomedicines are widely explored for precise drug delivery but are commonly produced by post-synthetic antibody conjugation, which limits reproducibility, scalability, and translational feasibility. Here, we report a conjugation-free nanoplatform formed by the one-step co-assembly of recombinant single-chain variable fragment-albumin fusion proteins (scFv-ALB) with poly(lactic-co-glycolic acid) (PLGA), termed the targeted fusion protein-polymer complex nanoplatform (T-CN). Using human epidermal growth factor receptor 2 (HER2) as a model target and paclitaxel (PTX) as a representative payload, we constructed T-CN@PTX. In this architecture, anti-HER2 scFv-ALB simultaneously directs nanoparticle assembly and tumor targeting, while PLGA reinforces structural integrity and enables efficient drug retention. In multiple in vitro and in vivo evaluations, T-CN@PTX exhibited superior stability, tumor accumulation, and antitumor efficacy compared with clinically used Nab-PTX and its targeted analog. Importantly, the modular design allows facile exchange of targeting ligands and therapeutic cargo, establishing T-CN as a versatile platform for scalable, cell-specific nanomedicine development with translational potential across diverse disease settings.