Activating upconversion nanoparticle-based photoresponsive nanovectors (UCPNVs) by upconversion visible light at low-power near-infrared (NIR) excitation can realize deeper biotissue stimulation with a minimized overheating effect and photodamage. Here, we demonstrate a facile strategy to construct new surface-decorated UCPNVs based on Passerini three-component reaction (P-3CR) in highly convenient and effective manners. Such UCPNVs materials have a tailored deprotecting wavelength that overlaps upconversion blue light. By using 3-perylenecarboxaldehyde, Tm3+/Yb3+ ion-doped UCNP-containing isocyanides, and antitumor agent chlorambucil as the three components, the resulting monodisperse UCPNV exhibits an efficient release of caged chlorambucil under a very low 976 nm power. This approach expands the synthetic toolbox to enable quick development of UCPNVs for UCNP-assisted low-power NIR photochemistry.