A Systematic Review of Toxicity, Biodistribution, and Biosafety in Upconversion Nanomaterials: Critical Insights into Toxicity Mitigation Strategies and Future Directions for Safe Applications

Abstract

Upconversion nanoparticles (UCNPs) are emerging as highly promising nanomaterials due to their exceptional optical properties, enabling diverse applications in biosensing, bioimaging, photodynamic therapy, and drug delivery. However, their potential toxicity should be comprehensively investigated for the safe utilization of UCNPs in several biomedical and environmental applications. This review systematically evaluates the current knowledge on UCNP toxicity from 2008 to 2024, focusing on key toxicological pathways, such as oxidative stress, reactive oxygen species (ROS) production, inflammatory responses, and apoptosis/necrosis, alongside their absorption, distribution, metabolism, and excretion processes and kinetics. Distinctively, this review introduces a bibliometric analysis of UCNP toxicity and biodistribution research, providing a quantitative assessment of publication trends, influential authors, leading institutions, funding agencies, and keyword occurrences. This approach offers a macroscopic perspective on the evolution and current landscape of UCNP safety research, a dimension largely unexplored in existing literature. Furthermore, the review combines mechanistic insights into UCNP toxicity with a critical evaluation of surface modifications, physicochemical properties, and administration routes, presenting a holistic framework for understanding UCNP biosafety. By combining bibliometric data with mechanistic insights, this review provides a data-driven perspective on UCNP-associated risks, actionable strategies for enhancing biosafety through surface engineering, and a forward-looking discussion on regulatory challenges and future directions for UCNP-based technologies. These findings bridge existing gaps in the literature and offer a comprehensive resource for researchers, clinicians, and policymakers, facilitating the safe development and utilization of UCNP-based technologies while establishing robust safety guidelines to mitigate adverse effects on human health and the environment.

Fig. 1.

Flowchart for selecting and screening literature.

Fig. 2.

The total number of UCNP and toxicity-related papers published between 2008 and 2024 in the Web of Science database.

Fig. 3.

The total number of UCNP and toxicity-related papers published in different countries.

Fig. 4.

Keyword map of publications on the toxicity of upconversion nanoparticles from 2008 to 2024.

Fig. 5.

Map of the predominant keywords of studies on upconversion nanoparticles and its biodistribution from 2008 to 2024.

Fig. 6.

Diagrammatic representation of toxicity assessment of upconversion nanoparticles via in vitro and in vivo studies showing the details of assays that can be performed in preclinical studies.

Fig. 7.

Molecular mechanism of toxicity of upconversion nanoparticles in a living system.

Fig. 8.

Upconversion nanoparticle inflammatory response pathways. The pathways include inflammatory response cytokine signaling (e.g., interleukin-6 [IL-6], tumor necrosis factor-alpha [TNF-α], and interferon-gamma [IFN-γ]), reactive oxygen species (ROS) production, and apoptosis. Additionally, the figure highlights the activation of macrophages, leading to nitric oxide (NO) and ROS production, and the roles of key genes and proteins such as nitric oxide synthase 2 (NOS2), protein kinase C delta (PRKCD), and signal transducer and activator of transcription 4 (STAT4).

Fig. 9.

Interaction of upconversion nanoparticles with living systems.

Fig. 10.

Factors responsible for the biosafety of upconversion nanoparticles.