Legumain protease-sheddable PEGylated, tuftsin-modified nanoparticles for selective targeting to tumour-associated macrophages

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Tumour-associated macrophages (TAMs) are key targets for cancer therapy.
• Achieving selective and efficient TAM targeting remains a significant challenge.
• Existing nanoparticle strategies often suffer from non-specific accumulation.

Purpose of the Study:

• To develop a novel nanoparticle platform for selective TAM targeting.
• To engineer nanoparticles that respond to the tumour microenvironment for enhanced drug delivery.
• To improve the specificity and efficiency of nanoparticle delivery to TAMs.

Main Methods:

• Constructed dual-functionalized nanoparticles (s-Tpep-NPs) with tuftsin (Tpep) and a protease-cleavable PEG layer.
• Utilized fluorescence resonance energy transfer and in vitro assays to confirm nanoparticle behavior.
• Evaluated nanoparticle accumulation and targeting efficiency in vivo compared to controls.

Main Results:

• s-Tpep-NPs responsively shed PEG, activating Tpep for TAM phagocytosis via Fc receptors.
• The cleavable PEG shield minimized non-specific accumulation in mononuclear phagocyte system organs.
• Demonstrated significantly enhanced tumour accumulation and improved TAM targeting specificity and efficiency.

Conclusions:

• The developed s-Tpep-NPs provide a robust nanoplatform for selective TAM targeting.
• This strategy offers a novel approach to overcome challenges in targeted cancer therapy delivery.
• The dual-functionalization enhances nanoparticle performance by responding to the tumour microenvironment.