Oriental Insight | Professors Xiaoyun Mao and Wen Xu’s Team Publishes a Comprehensive Review on Engineered Upconversion Nanoparticles for Precision Theranostics in Breast Cancer

Editor’s Note: Breast cancer remains the most common malignancy among women, with persistently high incidence and mortality rates. Its heterogeneity, drug resistance, and the toxicity associated with conventional therapies continue to challenge clinical management.In recent years, rare-earth-doped upconversion nanoparticles (UCNPs) have attracted growing attention in breast cancer research owing to their unique optical properties, tunable synthesis, and flexible functionalization strategies.Recently, the research teams led by Professor Xiaoyun Mao from the First Affiliated Hospital of China Medical University and Professor Wen Xu from the School of Physics and Materials Engineering, Dalian Minzu University, published a cover review in Theranostics titled 'Engineered Upconversion Nanoparticles for Breast Cancer Theranostics.'This review systematically summarizes the progress of UCNP-based strategies in breast cancer diagnosis and therapy, while also discussing challenges in clinical translation and future development directions.

Key Highlights

• Breast cancer remains a major public health challenge due to high incidence and mortality. Current diagnostic and therapeutic approaches face limitations such as poor real-time imaging, low treatment selectivity, and high systemic toxicity.

• UCNPs overcome the limitations of conventional fluorescent probes — they exhibit deep tissue penetration under near-infrared (NIR) excitation, resistance to photobleaching, minimal autofluorescence, and low phototoxicity.

• Through core–shell structural design and surface functionalization, a single UCNP can integrate multiple functions, including multimodal molecular imaging, phototherapy, drug/gene delivery, and immunotherapy.

• Clinical translation remains challenging, with issues such as batch variability, long-term biosafety, imaging/therapy optimization, and regulatory frameworks. Interdisciplinary collaboration will be key to advancing UCNPs from bench to bedside.

Breast Cancer Challenges and the Promise of UCNPs

Breast cancer’s complexity, resistance mechanisms, and limitations of traditional therapies demand innovative solutions. Upconversion luminescence—where multiple low-energy photons are absorbed and emitted as one higher-energy photon—offers such potential.Rare-earth elements, due to their rich energy levels, enable UCNPs to exhibit narrow emission bands, high photostability, and NIR excitation, making them ideal for biomedical applications. As nanotechnology advances, these materials have been tailored to the nanoscale, expanding their theranostic applications.Given the breast’s superficial anatomical position, NIR light penetration and low tissue absorption provide favorable conditions for UCNP-based imaging and therapy. Compared to traditional fluorescent probes, UCNPs’ anti-Stokes emission process reduces tissue autofluorescence and photodamage. Functionalization allows UCNPs to simultaneously carry targeting ligands, therapeutic agents, and imaging probes, enabling true integration of diagnosis and therapy.

01. Molecular Imaging

Imaging accuracy directly impacts clinical decision-making. UCNPs’ deep NIR penetration and low background noise make them excellent tools for molecular imaging.For instance, NaErF₄@NaYF₄ UCNPs modified with targeting peptides achieved an imaging depth of 9 mm in 4T1 breast tumor models and provided a 4× higher signal-to-background ratio than indocyanine green at 5 mm. They could distinguish benign from malignant tissue and identify microtumors as small as 2 mm, facilitating precision-guided tumor resection.In multimodal imaging, NaGdF₄:Nd@NaLuF₄-based probes combine upconversion fluorescence with MRI contrast. In 4T1 tumors, fluorescence signal-to-background ratio reached 8.2, while Gd³⁺ doping enhanced MRI contrast by 1.46× after six hours, enabling integrated structural and functional imaging.In sentinel lymph node mapping—vital for staging—CXCL-modified UCNPs demonstrated >92% sensitivity in differentiating metastatic from normal lymph nodes at 7 mm depth, aiding personalized surgical planning.

02. Biomarker Detection

Early molecular detection is crucial for improving prognosis. UCNP-based platforms enable high-sensitivity biomarker analysis through NIR excitation and multiplex narrow-band emission. Two main approaches exist:• Homogeneous assays based on resonance energy transfer (FRET) allow rapid “mix-and-read” detection by controlling donor–acceptor distance.• Heterogeneous assays use solid-phase interfaces for highly specific detection.In protein detection, NaGdF₄:Yb,Er@NaGdF₄ UCNPs conjugated with anti-ER, -PR, and -HER2 antibodies achieved simultaneous in situ imaging of multiple targets in MCF-7 cells. Quantification correlated well with Western blot results, with superior sensitivity for low-expression targets compared to immunohistochemistry.In serum biomarker assays, UCNP-based sensors exhibited detection limits as low as 6 pM for VEGF (recovery 98–113%) and 4.5 mU/mL for CA15-3, demonstrating promise for early screening. These platforms can also sensitively detect mRNA and circulating tumor DNA (ctDNA), expanding diagnostic potential.

03. Phototherapy

Photodynamic (PDT) and photothermal therapy (PTT) offer local, low-toxicity alternatives for cancer treatment, but are limited by shallow light penetration. UCNPs address this by converting NIR light into visible or UV emission to activate photosensitizers.For example, NaYF₄:Yb,Er@NaLuF₄ loaded with ZnPc reduced 4T1 cell viability to 38% under 980 nm irradiation and significantly inhibited tumor growth within 12 days. In PTT, UCNPs combined with gold nanoparticles or polydopamine achieved tumor ablation at 56.3°C, eradicating 4T1 tumors without recurrence.Dual PDT–PTT systems, such as NaGdF₄:Yb,Er@NaGdF₄ loaded with rose bengal and IR825, induced a 73.1% apoptosis rate, outperforming monotherapies.

04. Intelligent Drug and Gene Delivery

UCNP-based delivery systems enable stimuli-responsive, tumor-targeted drug release.• In light-triggered systems, UCNPs encapsulating nitrogen mustard derivatives released 68% of the drug under 980 nm light within 15 hours, versus only 3% in darkness.• In pH-sensitive systems, mSiO₂-coated UCNPs released >55% doxorubicin at pH 5.0 but only 35.2% at pH 7.4, minimizing toxicity to normal tissues.• For gene delivery, siRNA linked via disulfide bonds was effectively released in tumor environments rich in glutathione, reducing Bcl-2 mRNA levels by 50%.

05. Immunotherapy

Breast cancer immunotherapy faces challenges such as immune suppression and low response rates. UCNPs can enhance immune activation through several mechanisms.In dendritic cell (DC) vaccines, UCNPs loaded with ovalbumin enabled real-time tracking of DC migration and enhanced antigen-specific immune responses, promoting CD8⁺ T-cell proliferation and IFN-γ secretion.In immunogenic cell death (ICD), UCNP-mediated chemo-photodynamic therapy induced the release of calreticulin and ATP, activating DC maturation and T-cell infiltration.Furthermore, UCNPs combined with immune checkpoint inhibitors amplified systemic antitumor immunity. For instance, NaGdF₄:Yb,Er loaded with Ce6 and α-PD-1 antibody eradicated primary tumors and suppressed distant metastases through an abscopal effect.

06. Challenges and Future Perspectives

Despite their promise, UCNPs face hurdles before clinical translation. Scalable synthesis, batch reproducibility, and long-term biosafety remain major concerns. UCNPs tend to accumulate in the liver and spleen, raising chronic toxicity risks. Optimization of particle size, charge, surface ligands, and biodegradability will be essential.Furthermore, standardized evaluation criteria for nanomedicines are lacking. Discrepancies in testing methods and safety assessments hinder data comparability and clinical approval. Establishing international evaluation frameworks tailored for UCNP-based breast cancer applications is critical.Looking forward, with the convergence of materials science, pharmacology, and oncology, UCNPs are expected to evolve toward greater precision, safety, and efficacy, paving the way for next-generation breast cancer theranostics.