Rational Design of Dual-Targeted Nanomedicines for Enhanced Vascular Permeability in Low-Permeability Tumors.

Designing dual-targeted nanomedicines to enhance tumor delivery efficacy is a complex challenge, largely due to the barrier posed by blood vessels during systemic delivery. Effective transport across endothelial cells is, therefore, a critical topic of study. Herein, we present a synthetic biology-based approach to engineer dual-targeted ferritin nanocages (Dt-FTn) for understanding receptor-mediated transport across tumor endothelial cells. By leveraging a genetically engineered logic-gated strategy, we coassembled various Dt-FTn in with tunable ratios of RGD-targeting and intrinsic TfR1-targeting ligands. These Dt-FTn constructs were employed to investigate the interaction between receptor-mediated vascular permeability and dual-targeted nanomedicines in low-permeability tumors. Through machine learning-based single vessel analysis, we uncovered the crucial role of dual-receptor expression profiles in determining the vascular transport of dual-targeted nanomedicines in tumors with low permeability. Using a patient-derived colon cancer model, we demonstrated a proof-of-concept that the optimal proportions of dual ligands in these nanomedicines can be customized based on tumor cell receptor expression profiles. This study provides valuable insights and guiding principles for the rational design of dual-targeted nanomedicines for tumor-targeted delivery.