Upconversion nanoparticles (UCNPs) can convert tissue-penetrable nearinfrared light into UV emission, making them promising as transducers for photoactivation in biology. However, the choice of the UV emitting UCNPs is limited and their NIR-to-UV efficiency is low. G. Han and co-workers have addressed this issue by developing a family of CaF2-coated UCNPs with tunable UV enhancement. As reported on page 3213, such design outperforms known optimal UCNPs and in situ realtime live-cell photoactivation is recorded for the first time with such nanoparticles. This result is a potential game changer in photoactivation in living systems and a new tool for other biophotonic applications.