Synergistic therapy is an accepted method of enhancing the efficacy of cancer therapies. In this study, cypate-conjugated porous NaLuF4 doped with Yb3+, Er3+, and Gd3+ is synthesized and its potential for upconversion luminescence/magnetic resonance dual-modality molecular imaging for guiding oncotherapy is tested. Loading cypate-conjugated upconversion nanoparticles (UCNP-cy) with small interfering RNA gene against heat shock protein 70 (UCNP-cy-siRNA) enhances the cell damage. UCNP-cy-siRNA exhibits remarkable antitumor efficacy in vivo as a result of the synergistic effects of gene silencing and photothermal therapy, with low drug dose and minimal side effects. This result thus provides an explicit strategy for developing next-generation multifunctional nanoplatforms for multimodal imaging-guided synergistic oncotherapy.