Zwitterionic chitooligosaccharide-modified ink-blue titanium dioxide nanoparticles with inherent immune activation for enhanced photothermal therapy

Photothermal therapy (PTT) can trigger massive apoptosis of cancer cells, and this sharply increasing local apoptotic rate may recruit plenty of tumor-associated macrophages (TAMs). Although TAMs are recognized to display an M2-like subtype, which encourages tumor ontogenesis, they can be re-educated to a tumoricidal M1-like subtype by immunomodulatory reagents. Chitooligosaccharides (COSs) are endowed with immunomodulatory ability, but the positive electrical property limits their application; besides, their re-educating ability on TAMs is uncertain. Therefore, we proposed whether the combination of zwitterionic COS with a photothermal material can impair the undesirable tumor promotion of TAMs, thus enhancing the PTT treatment outcome. Herein, zwitterionic COS was obtained via the carboxymethylate method and then, the obtained COS was modified on the surface of ink-blue titanium dioxide (BTiO 2 ) with photothermal ability to synthesize BTC NPs. In vitro , the immunofluorescence staining and cell survival assays indicated that BTC NPs could re-educate 87% of the M2-like RAW264.7 macrophages stimulated by apoptotic tumor cell secretion and significantly inhibit the liver tumor cell proliferation. Notably, in a mouse H22 liver cancer model, compared with mono PTT with BTiO 2 , the PTT treatment of BTC could reverse the ratio of M2 : M1 from 3.3 : 1 to 0.5 : 1, thus leading to 20.7% increase in the tumor inhibition rate. In general, our study demonstrated that zwitterionic COS can act as a potent immune activator to re-educate TAMs to M1. Furthermore, equipping the photothermal material with zwitterionic COS can be a potential treatment paradigm to achieve more forceful PTT. Zwitterionic chitooligosaccharide-modified BTC NPs can re-educate TAMs to a tumoricidal M1 subtype, thus improving the antitumor effect of PTT.