Instituto Ramón y Cajal de Investigación Sanitaria

ConspectusLanthanide-doped upconverting nanoparticles (UCNPs) convert near-infrared (NIR) light into visible emission through multiphoton absorption processes. This property has made them useful tools for sensing and single-particle studies in biological environments. Their characteristic narrow emission lines, resistance to photobleaching, and the thermal coupling between the excited states of trivalent erbium (Er³⁺) have positioned UCNPs as a practical platform for intracellular thermometry despite their moderate sensitivity. Their response can be measured with standard microscopes using inexpensive NIR excitation sources, enabling experiments that are not easily achieved with other types of nanoscale thermometers. However, using UCNPs inside living cells also reveals important limitations because the intracellular medium is chemically complex and may alter the emission properties that form the basis of the thermal readout. Variations in local pH, ion concentration, viscosity, or molecular crowding can shift energy levels or modify nonradiative relaxation pathways. As a result, establishing the reliability of UCNP thermometry inside cells requires dedicated studies on particle stability, surface chemistry, and the influence of the cytoplasmic environment. Understanding these effects is essential for determining whether ratiometric UCNP thermometry can serve as a quantitative intracellular tool rather than only a qualitative indicator of heating. UCNPs have also enabled new single-particle experiments through optical trapping. A tightly focused NIR beam can immobilize an individual nanoparticle while simultaneously exciting its upconversion emission, allowing continuous monitoring of spectral changes, rotational dynamics, and local mechanical properties. These studies provide access to information that is hidden in ensemble measurements, such as particle-particle radiative interactions or the coupling between particle rotation/movement and local viscosity. Yet optical trapping also brings its own challenges: the forces acting on sub-100 nm UCNPs are modest, and trapping stability is strongly affected by laser-induced heating. Increasing dopant concentration improves confinement but raises thermal load, leading to a trade-off that must be carefully balanced. Approaches based on plasmonic enhancement are not suitable due to their additional heating, motivating interest in alternative photonic structures such as dielectric metasurfaces that could strengthen confinement while keeping temperatures low. Together, intracellular thermometry and single-particle trapping illustrate both the strengths and the current limitations of UCNPs. Their optical properties make them accessible probes for measuring local temperature and mechanical responses, but their performance heavily depends on the surrounding environment. In this Account, we summarize our efforts to understand UCNP behavior under realistic biological and trapping conditions. We discuss the stability of the thermometric response inside cells, the confinement-heating balance in optical traps, and the opportunities offered by single-particle measurements for studying light-matter interactions at the nanoscale. These considerations outline a path toward more reliable sensing and manipulation strategies based on UCNPs.

The TROPION-Breast01 study (NCT05104866) demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review (BICR) with the trophoblast cell-surface antigen 2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in patients with previously treated, inoperable/metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this article, we report results from the final overall survival (OS) analysis.

Patients with inoperable/metastatic HR-positive/HER2-negative breast cancer, who had disease progression on endocrine therapy and for whom endocrine therapy was unsuitable, and had received one to two prior lines of chemotherapy in the inoperable/metastatic setting were randomly assigned in a 1 : 1 ratio to Dato-DXd (6 mg/kg every 3 weeks) or ICC (eribulin/capecitabine/vinorelbine/gemcitabine). Dual primary endpoints were PFS by BICR and OS.

At data cut-off, median follow-up was 22.8 months. OS for the Dato-DXd versus ICC arm did not reach statistical significance (hazard ratio 1.01, 95% confidence interval 0.83-1.22, P = 0.9445). Use of ADCs (trastuzumab deruxtecan and sacituzumab govitecan) as subsequent therapy was imbalanced: 12.3% in the Dato-DXd arm versus 24.0% in the ICC arm. Secondary efficacy endpoints (PFS by investigator assessment, objective response rate, duration of response, disease control rate at 12 weeks, time to first and second subsequent therapy or death, and time to second progression or death) continued to favor Dato-DXd at this final analysis. The overall safety profile of Dato-DXd remained favorable compared with ICC, and no new safety signals were observed with longer follow-up.

TROPION-Breast01 met its dual primary endpoint of PFS by BICR. While there was no statistically significant improvement in the dual primary endpoint of OS with Dato-DXd versus ICC, subsequent ADC treatment may have affected OS results. The totality of efficacy and safety data supports Dato-DXd as a new treatment option for patients with previously treated, inoperable/metastatic HR-positive/HER2-negative breast cancer.