Protein stabilized polymeric nanoparticles inspired relay drug delivery for tackling post-chemotherapeutic metastasis

The pro-metastatic potential of chemotherapy limits its therapeutic benefits against invasive cancer. Herein, a protein stabilized polymeric nanoparticle inspired relay drug delivery platform was developed to address post-chemotherapeutic metastasis. An ROS-responsive Phenylboronic acid (PBA)-Rich cationic polymer (RPP) bridges Doxorubicin (Dox) coordination and Snail-targeted siRNA (siSnail) compression, and natural apolipoprotein A-I (apoA-I) is attracted by surface electron-deficient PBA moieties for nanoparticle shaping, drug biostability, and tumour-penetration. The spatially-separated structure enables a timing-controlled relay drug delivery in tumour cells, where Dox gives a prior release phase by acidity, and RPP polymer is subsequently disintegrated by concentrated ROS for rapid siSnail liberation. In dual therapy, Dox pre-treatment upregulated pro-metastatic factors and aggravated metastasis, but subsequent liberation by siSnail silenced the central metastatic regulator of Epithelial-mesenchymal transition (EMT). The terminal nanoparticles exhibited advanced therapeutic efficacy, achieving primary tumour shrinkage (tumour weight inhibition, TWI of ~86.15%) and complete metastatic nodule elimination. This work promises to improve the clinical benefits of chemotherapy against invasive cancer.