Upconversion nanoparticles (UCNPs) are excited in the near infrared (NIR) biological transparency window, but emits anti-Stokes shifted photons in the visible that are extremely photostable and ideally suited for biomedical imaging. First, we synthesize a UCNP-mOrange fluorescent protein conjugate that forms a Forster resonance energy transfer (FRET) pair with UCNP as the donor and mOrange as the acceptor to report intracellular pH by fluorescence imaging. The inactivity of the mOrange protein in acidic pH will decrease FRET efficiency making the emission green dominated by the UCNPs. In basic pH, the emission will be relatively orange. This is the first demonstration of ratiometric and self-ratiometric demonstration of intracellular pH imaging by the UCNPs. Next, we show a smart multifunctional nanoformulation of the UCNPs (NaGdF4: Yb, Er- 99mTc) using radioisotope labelling that shows potential for multimodal imaging using fluorescence, CT, and SPECT modalities. Intricate chemistry to engineer the UCNPs resulted in stabilizing the nanoformulation in physiological and aqueous environments with reproducible signal acquisition. This work gathers the expertise of physicists, chemists, and biologists in an interdisciplinary platform.