Dual-stimuli-responsive albumin-polyplex nanoassembly for spatially controlled gene release in metastatic breast cancer.

Stimuli-responsive polymeric nanoparticles are useful for overcoming challenges such as transfection efficiency and the specific and safe delivery of genes to cancer cells. Transfection outcomes can be improved through spatially and temporally controlled gene release. We formulated a nanoassembly comprising a disulfide-crosslinked polyethylenimine (ssPEI) conjugated with a tumor-specific cell-penetrating peptide (DS 4-3) (SPD) polyplex and bovine serum albumin (BSA)-loaded IR780 (BI) nanoparticle, thereby forming a dual-stimulus-triggered, tumor-penetrating and gene-carrying nanoassembly (BI-SPD) via electrostatic complexing. BI-SPD nanoassembly were composed of highly stable nanosized complexes with an average size of 457 ± 27.5 nm, exhibiting an up to two-fold enhanced transfection efficiency with no sign of potential cytotoxicity in breast cancer cells. Moreover, upon laser irradiation, a four-fold increase in transfection efficiency was achieved due to the rapid endosomal escape of polyplexes triggered by the local heat induced by the BI-SPD nanoassembly. Additionally, the high redox environment in tumor cells facilitated the disassembly of the SPD polyplex for efficient plasmid release in the cytosol. The BI-SPD nanoassembly also exhibited high penetration and enhanced photothermally triggered gene expression in the 4T1 spheroid model. This BI-SPD nanoassembly has the potential to enhance the expression of therapeutic genes in tumor models without causing significant toxicity to surrounding healthy tissues, since it has shown higher tumor targeting and accumulation in the 4T1 tumor in mice model.