Biochemical reprogramming of tumors for active modulation of receptor-mediated nanomaterial delivery

Here we report that reactive oxygen species (ROS) can reprogram cancer cells to increase the expression of specific receptors and modulate the delivery of nanomaterials. Gold and γ-polyglutamic acid (γ-PGA) hybrid nanoparticles (PGANP) were prepared via a facile single-step process. Gold nanoclusters in PGANP were dispersed within the tangled γ-PGA matrix of the nanoparticles. The condensed assembly of gold nanoclusters in γ-PGA matrix enabled the interparticle plasmon coupling effect, which lacks in single gold nanoparticles. Compared with gold nanoparticles of the similar sizes, PGANP showed significantly higher absorbance at near infrared (NIR) wavelength and light-to-heat converting ratios, resulting in greater temperature increase upon NIR light irradiation. Pretreatment of HeLa cancer cells with methylene blue (MB) generated reactive oxygen species. The ROS reprogrammed the cancer cells to express higher cell membrane levels of gamma glutamyl transferase (GGT), which is known to bind to γ-PGA of PGANP. MB pretreatment significantly enhanced delivery of PGANP to cancer cells. Cancer cells internalized PGANP to a greater extent and, were highly susceptible to irradiation with NIR light, which reduced cell viability to near zero. In vivo, MB pretreatment of HeLa xenograft mice increased the expression of GGT in tumor tissues. In mice pretreated with MB and exposed to NIR irradiation, PGANP treatment resulted in complete tumor ablation. The strategy of actively reprogramming tumor membrane levels of target receptors could be widely applied to overcome the heterogeneity of cancer cells. Although we used interparticle plasmon coupling effect-based PGANP for proving the concept of receptor-modulated delivery, this strategy could be broadly applicable to the active modulation of the receptor-mediated delivery of anticancer nanomaterials.