Size transformable organic nanotheranostic agents for NIR-II imaging-guided oncotherapy

Nanotheranostic agents combined the second near-infrared (NIR-II, 1000-1700 nm) fluorescence imaging with phototherapy strategy have attracted tremendous interest. However, the actual efficacy of NIR-II probes could be weakened by their limited accumulation and penetration in tumor tissues. Herein, a size-transformable NIR-II nanotheranostic agent (BBT-HASS@FPMPL NPs) is employed for simultaneously enhanced penetration and retention in deep tumor tissue to realize precise image and effective PTT therapy. BBT-HASS@FPMPL NPs were first formed by using hyaluronic acid (HA) chains and disulfide bonds as stimuli-responsive "lock" to efficiently load conjugated oligomer (BBTN⁺), and then folic acid (FA) modified polylysine (FPMPL) shell was stacked at the surface by electrostatic interaction. Dual targeting with HA and FA is expected to lead to more selective targeting and better accumulation of BBT-HASS@FPMPL NPs in tumor sites. Simultaneously, obvious particle size reduction and charge reversal can be triggered in acidic tumor microenvironment to achieve deep intratumor filtration through transcytosis. Following tumor penetration, size change was further initiated by overexpressed hyaluronidase and GSH in tumor. Free BBTN⁺ can be subsequently released from nanoparticles to promote specific intratumor retention, which synergistically enhance photothermal therapeutic efficacy. Owing to sufficient tumor accumulation and deep penetration, the NIR-II emission of BBTN⁺ could further be used for precise monitoring of subcutaneous tumor progression in mice for 6 days with just one dose injection. We expect that such nanotheranostic platform that combined the high resolution of NIR-II fluorescence with deep tumor penetration and long intratumor retention could be useful for real-time monitoring of tumor process, precise diagnosis, and enhanced phototherapy.