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By pairing a prostate-targeted nanogel with mRNA encoding a master regulator of cellular metabolism, researchers have suppressed prostate cancer growth in mice, highlighting a promising new approach for precision RNA therapeutics.

Prostate cancer is one of the most common cancers in men, yet treatment options become increasingly limited as tumours develop resistance to conventional therapies. Hoping to tackle the disease from an atypical angle, a study led by Professor David Carling and Dr Nazila Kamaly proposes a targeted mRNA therapy that restores levels of the metabolic regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), packaging the genetic instructions inside prostate-targeted polymer nanogels.

PGC1α is often described as the cell’s mitochondrial master regulator, coordinating the expression of genes involved in building and maintaining healthy mitochondria, and allowing cells to generate energy efficiently. At first glance, boosting mitochondrial function in cancer seems counterintuitive. Cancer cells need energy to proliferate, so why give them more mitochondria?

The answer lies in how prostate cancer evolves. As tumours become more aggressive, they undergo substantial metabolic rewiring. Losing PGC1α helps to drive this shift towards a state favouring invasion and metastasis. Therefore, restoring its activity appears to reverse some of this rewiring, pushing cancer cells towards a less proliferative phenotype. But delivering such a large intracellular protein directly is not feasible. Instead, by delivering mRNA encoding for PGC1α, cells can transiently produce the therapeutic protein themselves.

While mRNA medicines have transformed vaccinology, extending this technology to cancer has been hampered by the difficulty of transporting mRNA safely through the body and releasing it inside target cells. Although lipid nanoparticles dominate current mRNA therapeutics, they naturally accumulate in the liver, making tissue-specific delivery challenging. To address this, the team engineered prostate-targeted, degradable polymeric nanogels crosslinked with disulphide bonds. These nanogels protect the mRNA cargo during circulation but are designed to degrade once inside the cancer cells, where intracellular glutathione concentrations are higher than in the bloodstream. This reducing environment breaks the disulphide bonds and triggers mRNA release. The researchers further functionalised the nanogels with a peptide targeting the prostate-specific membrane antigen, a receptor highly expressed on prostate cancer cells, enabling specific uptake by tumours.

Following uptake, nanogels enabled sustained production of PGC1α and an increase in mitochondrial proteins, indicating that the cells had begun rebuilding their mitochondrial network. In mice bearing human prostate cancer xenografts, the PSMA-targeted nanogels preferentially accumulated in the tumours and reduced them by 73.4 % in comparison to untreated controls, while the animals showed no evidence of systemic toxicity, suggesting the delivery system was well tolerated.

The work highlights how advances in chemistry are expanding what is possible with RNA medicines. “These results are extremely encouraging and pave the way for further studies aimed at translating our findings into the clinic”, says Professor David Carling, who was involved in the work.

By combining programmable mRNA therapies with smart, stimuli-responsive materials that release their cargo only after reaching tumour cells, researchers are beginning to tackle diseases that have so far remained beyond the reach of conventional RNA delivery systems.

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