Redox-responsive nanogels for targeted nucleic acid delivery: a potential approach for metabolically reprogramming prostate cancer
File(s)
Author(s)
Dabas, Rupali
Type
Thesis
Abstract
Prostate cancer (PCa) is now the most commonly diagnosed cancer among men in the UK and US. Increasing evidence implicates metabolic dysregulation as a critical driver of disease progression. AMP-activated protein kinase (AMPK), a central regulator of cellular energy homeostasis, has been shown to suppress PCa growth in vivo through induction of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). PGC1α, acting via oestrogen-related receptor alpha (ERRα), promotes oxidative metabolism and mitochondrial biogenesis while inhibiting metastatic programs. This work investigates the therapeutic potential of PGC1α overexpression via mRNA delivery. To this end, a library of redox-responsive polymeric nanogels (NGs) were synthesised through combinatorial free-radical polymerisation to entrap and deliver RNA cargo. Following systematic optimisation, a lead formulation was identified, exhibiting superior RNA encapsulation, cytosolic release, and transfection efficiency relative to commercial transfection agents. Functionalisation of these NGs with a peptide targeting prostate-specific membrane antigen (PSMA) enabled selective delivery of PGC1α and its N-terminal isoform (NT-PGC1α) to PCa cells. Various bioassays were used to confirm sustained PGC1α expression, and increased mitochondrial protein content, indicative of enhanced mitochondrial biogenesis. Transcriptomic analysis demonstrated activation of tumour suppressor pathways and suppression of proliferative markers, consistent with metabolic rewiring and growth inhibition. In vivo, systemic administration of NT-PGC1α-loaded PSMA-NGs resulted in tumour selective accumulation and significant suppression of xenograft growth, with no overt systemic toxicity. This study presents the first example of a prostate-targeted, disulfide-crosslinked nanogel system for mRNA-mediated metabolic reprogramming in PCa, and highlights its promise as a platform for future RNA-based cancer therapies.
Version
Open Access
Date Issued
2025-08-21
Date Awarded
01/12/2025
License URL
Advisor
Carling, David
Kamaly, Nazila
Sponsor
Medical Research Council (Great Britain)
Imperial College London
Publisher Department
Institute of Clinical Sciences
Department of Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)