Preprint For: Revisiting the Potential of Upconversion Nanoparticles in Biomedical Applications: Advances and Emerging Perspectives

Upconversion nanoparticles (UCNPs) have evolved from niche photophysical systems into multifunctional platforms with growing relevance in biomedicine. Their ability to convert near-infrared excitation into higher-energy emission enables deep tissue interrogation with minimal background and high photostability, offering clear advantages over conventional probes. This review revisits the field from a design-oriented perspective, reflecting how recent advances in synthesis, photophysical understanding, and nanoengineering have reshaped the relationship between UCNP structure and biomedical performance. Combining properties and applications highlight how rational control over architecture and interfaces governs functionality in complex biological environments. This evolving framework is discussed across major application domains, alongside emerging directions that extend UCNPs beyond passive imaging toward active and programmable systems. Despite substantial progress, key challenges persist in achieving high brightness under safe excitation, ensuring predictable biological behavior, enabling safe clearance, and improving reproducibility. Addressing these limitations through integrated material and system-level design will be critical for translating UCNPs into reliable biomedical technologies.