RNA that knows where to go: the rise of targeted delivery

Researchers are developing new ways to guide RNA medicines directly to diseased cells, improving precision and reducing side effects. Targeted delivery is emerging as the next major advance in RNA therapeutics. N4 Pharma and SRI International are addressing this through Nuvec^®, a silica-based nanoparticle system built to deliver RNA precisely to diseased cells.

The work highlights an important advance in the ongoing effort to make RNA therapeutics more targeted, stable and scalable. The global RNA therapeutics market, valued at $13.7 billion in 2023 and forecast to reach $18 billion by 2028, continues to expand. Yet developers face persistent barriers in manufacturing and targeted delivery, limitations that, if overcome, could dramatically change how RNA medicines are used in oncology.

It was with this goal in mind that N4 Pharma, began exploring opportunities to combine the company’s Nuvec^® delivery platform with SRI International’s peptide-targeting technology. The partnership aims to address one of RNA therapeutics’ toughest challenges – delivering genetic medicines precisely to cancer cells while limiting effects on healthy tissue.

From concept to collaboration

SRI International, a US-based research institute known for its pioneering work in biotechnology and materials science, has developed peptide-based molecules that recognise and bind to distinct cell surface receptors. Nuvec^®, N4 Pharma’s silica-based nanoparticle platform, provides a complementary way to transport RNA or small interfering RNA (siRNA) payloads into those same cells.

Together, the two technologies aim to extend the reach of RNA therapeutics beyond tissues like the liver and central nervous system, where most approved RNA medicines are currently delivered. By combining SRI’s targeting peptides with Nuvec^®’s delivery system, the collaboration seeks to enable precise RNA delivery to a wider range of diseases, including solid tumours.

The Nuvec^® difference

“Nuvec^® is a unique silica nanoparticle, with a spiky surface. The total surface area of 2g of Nuvec® is approximately the size of a basketball court, giving a large surface area to carry multiple cargo, including RNA and targeting moieties” comments Dr Fiona McLauglin, Head of Research and Development at N4 Pharma.

Unlike lipid nanoparticles, which dominate the RNA delivery field, Nuvec^® is built from inorganic silica. Its spiky surface provides a vast area for binding RNA, siRNA and other targeting molecules. “The ability to add RNA/siRNA as well as targeting moieties means that Nuvec^® can be directed towards cancer cells, delivering cargo directly to kill cancer cells and spare non-cancer cells.”

This dual capability – delivery and targeting – sets Nuvec^® apart. By adjusting which targeting peptides are attached, researchers can adapt the platform for different tumours or disease tissues.

Proof of concept: targeting non-small cell lung cancer

The team’s recent findings demonstrate that Nuvec^® can selectively deliver therapeutic RNA to non-small cell lung cancer (NSCLC) cells. For McLaughlin, this is a pivotal step.

“This is a very significant finding. Being able to target RNA to disease specific sites in the body (outside of opportunities targeting the liver) is the holy grail.”

She points out that, to date, approved oligonucleotide therapies have been confined to either the central nervous system or the liver. Expanding delivery to solid tumours could enable a wider range of therapeutic applications.

“NSCLC remains a huge unmet need and despite many approved drugs, resistance to therapy is a major obstacle. The ability to target both wild type and mutant proteins in NSCLC using siRNA would open up a number of therapeutic opportunities.”

Laboratory studies confirmed that when Nuvec^® was functionalised with a peptide binding to the αvβ6 adhesion molecule – a protein over-expressed in epithelial cancers – its siRNA payload was taken up only by targeted cancer cells, not by controls. This specificity suggests the platform could be tuned to reach other cancers in which αvβ6 is present, such as breast, pancreatic and prostate tumours.

Broadening potential across oncology

“This is something that we are actively exploring. Our data to date is in cell-based assays and we are looking at opportunities to translate this in vivo and demonstrate targeting to solid tumours including NSCLC.”

Translating these in-vitro results into animal models is the next critical step. McLaughlin notes that pancreatic cancer is a natural extension of the research.

“Pancreatic cancer is another high unmet need area where tumours are often diagnosed late in the disease and therefore difficult to treat. Targeting siRNA directly to a pancreatic tumour would open up a number of therapeutic opportunities.”

The potential of a modular, adaptable delivery system is clear: a single platform could serve multiple indications simply by changing the targeting peptide or RNA sequence.

Tackling RNA delivery challenges

One reason RNA therapeutics remain challenging to develop lies in their physical instability and immunogenic potential. Lipid-based carriers can degrade over time or trigger unwanted immune responses. Nuvec^®’s inorganic composition may help address both issues.

“Our Nuvec^® silica nanoparticles are quite different from lipid nanoparticles as they are inorganic and as such are very stable. Manufacturing of silica nanoparticles is straight forward and readily scalable.”

McLaughlin adds that while immunogenicity can only be fully assessed in humans, preclinical studies are encouraging.

“Immunogenicity can only be truly tested when in humans, however we have no flags to date from studies where Nuvec^® has been dosed multiple times in immunocompetent mice.”

Next steps and milestones

The collaboration with SRI has generated data that will now guide the next stage of validation.

“We are looking to validate this result in a mouse model of NSCLC, where we can demonstrate that our targeted Nuvec^® has the appropriate drug properties to deliver RNA cargo to a tumour in vivo and ultimately result in tumour reduction.”

Alongside this work, N4 Pharma is exploring other solid tumour indications that might be addressable using the same approach. The aim is to build a data package strong enough to support future licensing discussions or internal development programmes.

Expanding RNA therapeutics

The RNA therapeutics field is expanding quickly, yet targeted delivery remains one of the main barriers to wider clinical use. The N4–SRI results suggest a way to address that challenge.

“In the near term we are concentrating on building a comprehensive data set, building on the great data generated with SRI, to demonstrate the superior performance of Nuvec^® as an RNA delivery platform.”

McLaughlin expects this work to support future licensing agreements and partnerships.

“We anticipate that these data will lead to licensing deals for the Nuvec^® platform with larger partners. In the longer term we aim to build a proprietary pipeline of novel RNA therapeutics differentiated by the Nuvec^® delivery system.”

The company’s lead internal programme – an orally delivered treatment for inflammatory bowel disease – is in early preclinical development, with further efficacy data expected from established animal models.

Looking to the next decade

“Overall, the field of RNA-based therapeutics has expanded dramatically in the last 5 years and shows tremendous potential to start addressing common ailments and difficult-to-treat diseases.”

As the therapeutic potential of RNA expands, so too does the need for delivery systems that can overcome biological barriers safely and efficiently. Nuvec^®’s silica-based architecture, combined with SRI’s targeting technology, offers a glimpse of how future treatments could reach specific tumour sites with greater precision.

If successful, such delivery systems could expand RNA therapy beyond injection, enabling more accessible treatment options, including oral formulations for certain conditions.