NaYbF4:Tm@NaYF4:Yb/Er upconversion nanoparticles are synthesized and then integrated with light-sensitive nitric oxide (NO) donors (Roussin's black salt) to construct a novel near-infrared (NIR)-triggered on-demand NO delivery platform. This nanocompound can absorb 980 nm NIR photons, convert them into higher energy photons and then transfer the energy to the NO donors, resulting in an efficient release of NO. By manipulating the output power of the 980-nm NIR light, NO-concentration-dependent biological effects for cancer therapy can be fine-tuned, which is investigated and confirmed in vitro. High concentrations of NO can directly kill cancer cells and low concentrations of NO can act as a potent P-glycoprotein (P-gp) modulator to overcome multi-drug resistance (MDR) if combined with chemotherapy.