Despite the tremendous theranostics potential of nano-scale drug delivery system (NDDS) in oncology field, their tumor-targeting efficiency and safety remain major challenges due to their proneness of off-target accumulation through widespread vascular endothelial gaps (up to 1 μm). To address this problem, in this research, micro-sized cellular platelet “ghosts” (PGs, 1.32 μm, platelet without inner granules and coagulation) were employed as carriers to ship hollow gold nanoparticles (HGNs, 58.7 nm), forming a hierarchical biosafe system (PG@HGNs) to reduce normal tissue interception and enhance tumor targeting delivery of HGNs for improved photothermal therapy. PGs were prepared by an optimized “swelling-extrusion-elution” method, HGNs were loaded in PGs (PG@HGNs) through a “hypotonic dialysis” method and the safety and biodistribution of the system was evaluated in vitro and in vivo. In in vitro condition that stimulated the tumoral vessel acidic microenvironment (pH = 6.5), PG@HGNs were demonstrated with enhanced membrane fluidity through down-regulation of the glycoprotein Ib expressed on the PGs. This change induced a burst release of nano-sized HGNs which were capable to traverse vascular endothelium layer on a tumor-endothelial cell transwell model, whilst the micro-sized PG carriers were intercepted. In comparison to nano-sized platelet membrane-coated carriers (PM@HGNs), PG@HGNs showed enhanced internalization and cytotoxicity to 4T1 cells. In animal models, PG@HGNs remarkably prolonged circulation most likely due to the presence of “self-recognition” receptor-CD47 of PGs, and effectively reduced normal tissue interception via the micro-scale size effect. These both contributed to the significantly improved tumor targeting efficiency of HGNs. PG@HGNs generated the greater antitumor photothermal efficacy alongside safety in the animals compared to PM@HGNs. Collectively, this study demonstrated the potential of the micro-scale PGs equipped with adjusted membrane GP Ib as biosafe vehicles for HGNs or possibly other nanodrugs.

The statement of significance

Despite the tremendous theranostics potentials, the safety and tumor-targeting efficiency of nano-scale drug delivery systems (NDDS) are compromised by their undesirable accumulation in normal tissues with widespread vascular endothelial gaps, such as many tumor-targeted NDDSs still accumulated much in liver and/or spleen. Herein, we explored a micro-nano biomimetic cascade delivery system to address the above drawbacks. By forming a hierarchical biosafe system, micro-sized platelet “ghost” (PGs, 1.32 μm) was employed as tumor-targeted delivery carrier to transport hollow gold nanoparticles (HGNs, 58.7 nm). It was demonstrated that this micro-size system could maintain platelet membrane structure thus prolong in vivo circulation, while avoiding extravasation into normal tissues. PG@HGNs could sensitively respond to the acidic microenvironment near tumor vessel via down-regulation of glycoprotein Ib and rapidly release “nano-bullets”-HGNs to further penetrate into the tumor tissues through EPR effect, thus enhancing photothermal efficacy generated by HGNs under NIR irradiation. Collectively, the micro-scaled PGs could be biosafe vehicles for improved tumor-targeted delivery of HGNs or possibly other nanodrugs.