ONOO^- generator constructed with a small molecule photosensitizer and photoinduced NO donor for tumor therapy

Multimodal synergistic therapy is an effective means to improve therapeutic outcomes against cancer. Herein, a nanotherapeutic platform for highly efficient photodynamic and NO synergistic therapy through the generation of peroxynitrite (ONOO^-) was constructed. Specifically, a new small molecule photosensitizer (DMATPE-MN) and photoinduced NO donor (NTA-CN) were subtly designed, which displayed similar light absorption in the visible light region. Under the same light irradiation, DMATPE-MN and NTA-CN can generate a superoxide anion free radical (O₂˙^-) and an NO radical, respectively. Then, NTA-CN and DMATPE-MN were integrated together into nanocarriers formed from amphiphilic pillararene (WP5-PEG-OH) through host-guest and hydrophilic/hydrophobic mechanisms. Exhilaratingly, the NO generation efficiency of NTA-CN can be significantly improved after host-guest complexation with WP5-PEG-OH. It is even more exciting that the formed nanodrug WP5-NTA/MN can generate ONOO^- after light irradiation. As a result, WP5-NTA/MN exhibited outstanding biocompability and showed high tumor cell lethality under both normoxic and hypoxic conditions. Furthermore, the experimental results in vivo also demonstrated its good biosafety and ability to inhibit tumor growth. Thus, we provided a highly promising nanoplatform for multimodal synergistic therapy.