NIR light-activated dual-modality cancer therapy mediated by photochemical internalization of porous nanocarriers with tethered lipid bilayers

To overcome endo/lysosomal restriction as well as to increase the clinical availability of nanomedicine, we report on a NIR stimuli-responsive nanoplatform based on mesoporous silica nanoparticles tethered with lipid bilayers (MSN@tLB) for chemotherapy and photodynamic dual-modality therapy. In this nanosystem, a hydrophilic drug molecule zoledronic acid (ZOL) was first incorporated into the MSN core with modifications of hyperbranched polyethylenimine (PEI). To prevent the leakage of the payload, the LB shell was covalently tethered onto the MSN core via the PEI cushion which can greatly enhance the stability of the LB. Meanwhile, a hydrophobic photosensitizer IR-780 iodide was introduced into the hydrophobic compartment to endow the system with photo-activation properties. The as-prepared MSN-ZOL@tLB-IR780 possesses high dispersion stability stemming from the LB, as well as negligible cytotoxicity. After cellular internalization and endo/lysosomal capture of the nanoparticles, photochemical internalization (PCI) mediated simultaneous cargo release and endo/lysosomal escape were achieved by local ROS production upon 808 nm irradiation, thus leading to highly efficient chemo-photodynamic therapy on cancer cells in vitro. Such a system presents a sophisticated platform that integrates biocompatibility, spatiotemporal control, NIR-responsiveness, and synergistic therapies to promote cancer therapy.