Homologous-targeting biomimetic nanoparticles for photothermal therapy and Nrf2-siRNA amplified photodynamic therapy against oral tongue squamous cell carcinoma

Abstract Photothermal therapy (PTT) and photodynamic therapy (PDT) have some advantages such as site selectivity, non- or little-invasive property and negligible drug resistance for treatment of oral tongue squamous cell carcinoma (OTSCC). However, the activation of intracellular antioxidant responses will partly counteract anticancer effects of PDT. As a well-known redox-regulated transcription factor, Nrf2 has been found to participate in the resistance of tumor cells against PDT. Hereon, a biomimetic nanoparticle system was designed for co-loading and targeted delivery of photosensitizer indocyanine green (ICG) and Nrf2-siRNA, thus hope to achieve synergistic effects of PTT and amplified PDT in OTSCC. Poly(β-amino ester) (PBAE)/poly lactic-co-glycolic acid (PLGA) blended nanoparticles co-loaded with ICG and Nrf2-siRNA were prepared and then encapsulated within the vesicles of cancer cell membrane (CCM) specifically derived from homologous OTSCC, thus obtained biomimetic nanoparticles named as M@PPI-siRNA. Both in vitro and in vivo, M@PPI-siRNA nanoparticles exhibited strong OTSCC-targeting ability due to tumor-homing effect of homologous CCM. Upon laser irradiation at 808 nm, M@PPI-siRNA nanoparticles significantly down-regulated the expressions of Nrf2 and its regulated genes, glutamate-cysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) that play important roles in ROS detoxification, and subsequently indirectly enhanced PDT anticancer effects by maintaining the accumulation of intracellular ROS. Through cooperation of PTT and Nrf2-siRNA amplified PDT, M@PPI-siRNA nanoparticles significantly inhibited the proliferation and induced the apoptosis of OTSCC cells, and also notably suppressed tumor growth and angiogenesis in OTSCC tumor-bearing mice. In summary, this study provides a promising OTSCC-targeted delivery system for both photosensitizer and gene, and also confirms that Nrf2-siRNA is an efficient synergist for amplifying PDT.