Frequency shift surface-enhanced Raman scattering (SERS) achieves multiplex microRNA sensing for early serological diagnosis of, and discrimination between, primary liver cancers in a patient cohort for whom only biopsy is effective clinically. Raman reporters microprinted on plasmonic substrates shift their vibrational frequencies upon biomarker binding with a dynamic range allowing direct, multiplex assay of serum microRNAs and the current best protein biomarker, α-fetoprotein. Benchmarking against current gold-standard polymerase chain reaction and chemiluminescence methods validates the assay. The work further establishes the frequency shift approach, sensing shifts in an intense SERS band, as a viable alternative to conventional SERS sensing which involves the more difficult task of resolving a peak above noise at ultralow analyte concentrations.

Manganese dioxide (MnO2) nanostructures have aroused great interest among analytical and biological medicine researchers as a unique type of tumor microenvironment (TME)-responsive nanomaterial. However, reliable approaches for synthesizing yolk–shell nanostructures (YSNs) with mesoporous MnO2 shell still remain exciting challenges. Herein, a YSN (size, ∼75 nm) containing a mesoporous MnO2 shell and Er3+-doped upconversion/downconversion nanoparticle (UCNP) core with a large cavity is demonstrated for the first time. This nanostructure not only integrates diverse functional components including MnO2, UCNPs, and YSNs into one system but also endows a size-controllable hollow cavity and thickness-tunable MnO2 layers, which can load various guest molecules like photosensitizers, methylene blue (MB), and the anticancer drugs doxorubicin (DOX). NIR-II fluorescence and photoacoustic (PA) imaging from UCNP and MB, respectively, can monitor the enrichment of the nanomaterials in the tumors for guiding chemo-photodynamic therapy (PDT) in vivo. In the TME, degradation of the mMnO2 shell by H2O2 and GSH not only generates Mn2+ for tumor-specific T1-MR imaging but also releases O2 and drugs for tumor-specific treatment. The result confirmed that imaging-guided enhanced chemo-PDT combination therapy that benefited from the unique structural features of YSNs could substantially improve the therapeutic effectiveness toward malignant tumors compared to monotherapy.

Designing luminescence lifetime sensors in the second near‐infrared (NIR‐II) window is a great challenge due to the difficult structural construction. Here, we report a tumor redox responsive and easily synthesized material, amorphous manganese oxide (MnOx) with indirect band gap of 1.02 eV, as an energy acceptor to build a luminescence resonance energy transfer (LRET) toolbox for universally regulating NIR‐I to NIR‐II luminescence lifetimes of lanthanide nanoparticles, in which energy transfer is based on matched energy gap instead of conventional overlapped spectra. We further utilize ytterbium (Yb3+)‐doped YbNP@MnOx as an NIR‐II luminescence lifetime sensor to realize in vitro quantitative redox visualization with relative errors under 5 % in samples covered with mouse skin. Furthermore, HepG2 cells and tumors with high redox state have been accurately distinguished by NIR‐II luminescence lifetime imaging. The quantified intracellular and intratumor glutathione (GSH) levels are highly consistent with the commercial kit results, illustrating the reliable redox visualization ability in biological tissue.

Cyanine dye-coordinated upconversion nanoparticles were developed for real-time monitoring drug-induced hepatotoxicity in vivo by ratio-fluorescence and photoacoustic imaging of peroxynitrite.