pH-responsive nanocomplex for active transport of aPD-1 and PTX to enhance cancer chemoimmunotherapy

Immune checkpoint blockade (ICB) therapy has emerged as a promising avenue for the treatment of malignant tumors. Nonetheless, the efficacy of this approach is constrained by low anti-tumor immunity and restricted intratumoral delivery of immune checkpoint inhibitors (ICIs) in solid tumors. In this study, a pH-responsive nanocomplex (BRM/PTX/aPD-1) was developed for the active transport of aPD-1 and PTX, thereby enhancing cancer chemoimmunotherapy. BRM/PTX/aPD-1 was prepared by using dynamic and reversible benzoic-imine bonds cross-linked bovine albumin (BSA), anti-PD-1 antibody (aPD-1) and PTX-loaded polylysine dendrimers. In the acidic tumor microenvironment, BRM/PTX/aPD-1 exhibited a charge reversal from negative to positive due to the hydrolysis of the β-carboxylic amide structure, which triggered cation-induced transcytosis. This process enabled active transport of adequate amounts of BRM/PTX/aPD-1 to the tumor parenchyma, where it was degraded by further hydrolysis of benzoic-imine bonds and effectively released aPD-1 and PTX. The nanocomplex demonstrated notable intratumoral permeability both in vitro and in vivo, particularly enhancing the delivery of aPD-1. Additionally, the nanocomplex showed robust anti-tumor activity in an orthotopic breast cancer model, significantly inhibiting tumor proliferation and preventing the progression of lung metastasis. This pH-responsive nanocomplex presents a promising platform for improved intratumoral delivery of ICIs and emerges as a practical solution for overcoming tumor immunosuppression.