• uponversion nanoparticles;
  • pH sensitive;
  • charge switching;
  • photodynamic therapy;
  • dual-modal imaging


Photodynamic therapy (PDT) based on upconversion nanoparticles (UCNPs) can effectively destroy cancer cells under tissue-penetrating near-infrared light (NIR) light. Herein, we synthesize manganese (Mn2+)-doped UCNPs with strong red light emission at ca. 660 nm under 980 nm NIR excitation to activate Chlorin e6 (Ce6), producing singlet oxygen (1O2) to kill cancer cells. A layer-by-layer (LbL) self-assembly strategy is employed to load multiple layers of Ce6 conjugated polymers onto UCNPs via electrostatic interactions. UCNPs with two layers of Ce6 loading (UCNP@2xCe6) are found to be optimal in terms of Ce6 loading and 1O2 generation. By further coating UCNP@2xCe6 with an outer layer of charge-reversible polymer containing dimethylmaleic acid (DMMA) groups and polyethylene glycol (PEG) chains, we obtain a UCNP@2xCe6-DMMA-PEG nanocomplex, the surface of which is negatively charged and PEG coated under pH 7.4; this could be converted to have a positively charged naked surface at pH 6.8, significantly enhancing cell internalization of nanoparticles and increasing in vitro NIR-induced PDT efficacy. We then utilize the intrinsic optical and paramagnetic properties of Mn2+-doped UCNPs for in vivo dual modal imaging, and uncover an enhanced retention of UCNP@2xCe6-DMMA-PEG inside the tumor after intratumoral injection, owing to the slightly acidic tumor microenvironment. Consequently, a significantly improved in vivo PDT therapeutic effect is achieved using our charge-reversible UCNP@2xCe6-DMMA-PEG nanoparticles. Finally, we further demonstrate the remarkably enhanced tumor-homing of these pH-responsive charge-switchable nanoparticles in comparison to a control counterpart without pH sensitivity after systemic intravenous injection. Our results suggest that UCNPs with finely designed surface coatings could serve as smart pH-responsive PDT agents promising in cancer theranostics.