Nanobody-Decorated Lipid Nanoparticles for Enhanced mRNA Delivery to Tumors In Vivo

Pol Escudé Martinez de Castilla ¹, Vincenzo Verdi ^2,3, Willemijn de Voogt ¹

⁰CDL Research, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.

Advanced Healthcare Materials +

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July 4, 2025

View abstract on PubMed

Summary

Researchers developed targeted lipid nanoparticles (LNPs) for prostate cancer (PCa) therapy. These anti-PSMA LNPs show promise for delivering mRNA to PSMA-positive cancer cells, though challenges remain for in vivo delivery.

Area Of Science

Oncology
Nanotechnology
Biochemistry

Background

Prostate cancer (PCa) is a leading cause of cancer death globally, with a significant portion progressing to incurable castration-resistant PCa.
Castration-resistant PCa cells frequently overexpress prostate-specific membrane antigen (PSMA), presenting a potential therapeutic target.
RNA-based therapeutics offer a promising avenue for cancer treatment.

Purpose Of The Study

To develop and evaluate PSMA-targeted lipid nanoparticles (LNPs) for delivering RNA therapeutics to prostate cancer cells.
To investigate the efficacy of anti-PSMA LNP decoration and its impact on cellular uptake and mRNA transfection.
To assess the in vitro and in vivo performance of these targeted LNPs in preclinical models.

Main Methods

Lipid nanoparticles (LNPs) were decorated with anti-PSMA nanobodies via click chemistry.
Direct stochastic optical reconstruction microscopy (dSTORM) and cluster analysis were used to confirm nanobody surface presentation.
In vitro and in vivo studies were conducted using PSMA-positive cancer cells, Zebrafish xenografts, and mouse xenograft models.

Main Results

Surface decoration confirmed at least one nanobody on 80% of LNPs.
Anti-PSMA LNPs demonstrated enhanced and specific uptake and mRNA transfection in PSMA+ cancer cells in vitro.
These targeted LNPs showed effective mRNA delivery in Zebrafish models but limited functional delivery in mouse models.
Systemic administration in mice led to increased LNP accumulation but not successful mRNA delivery.

Conclusions

PSMA-targeted LNPs show potential for specific delivery of mRNA therapeutics to advanced prostate cancer.
The study highlights the successful in vitro and Zebrafish model validation of targeted LNP delivery.
Challenges in achieving functional mRNA delivery in vivo, particularly in mouse models, require further investigation and optimization.

Keywords:

mRNA‐lipid nanoparticles nanobody prostate cancer prostate specific membrane antigen (PSMA) targeted delivery