Stimuli-sensitive PEGylated sheddable nanoparticles for the delivery of siRNA to cancer cells

Annarita Velleca – Fellow researcher, Department of Pharmacy University Federico II of Naples; Mariano Stornaiuolo – Full professor, Department of Pharmacy University Federico II of Naples; Simona Laurino – Researcher, IRCCS-CROB Referral cancer center of basilicata; Sabino Russi – Researcher, IRCCS-CROB Referral cancer center of basilicata; Geppino Falco – Full professor, Department of Biology University Federico II of Naples; Fabiana Quaglia – Full professor, Department of Pharmacy University Federico II of Naples; Claudia Conte – Associate Professor, Department of Pharmacy University Federico II of Naples

Introduction:

PEGylated NPs offer significant advantages for siRNA delivery, including prolonged circulation and reduced immune clearance. However, PEG coating creates a critical barrier that hinders cellular uptake. Stimuli-responsive NPs represent a strategy to overcome the "PEG dilemma”¹. We designed the NPs to retain the PEG  during circulation but selectively shed it upon specific tumour microenvironment triggers, such as elevated glutathione or external infrared light². PEG removal exposes the NP core boosting tumour cell uptake, endosomal escape, and siRNA release. This platform enables circulation stealth without compromising intracellular delivery enhancing precision cancer nanomedicine.