Recent advances in biotechnology and genetic engineering have produced new therapeutics and treatment modalities for many diseases and created an emphasis on effectively delivering novel drugs to their target destinations. RNA-based therapeutics are poised to revolutionize treatment options for a variety of genetic diseases that had until recently been untreatable. However, delivering fragile therapeutic RNA to cellular and subcellular targets remains daunting.

The various delivery vehicles for RNA therapeutics can be broadly categorized into viral and nonviral systems. Viral delivery is currently the most popular and sophisticated method for the delivery of gene therapies. On the other hand, nonviral delivery systems include liposome, niosome,1 and lipid nanoparticles2 (LNPs).

Concerns exist regarding the safety of viral delivery systems although AAV delivery is widely used and considered the safest of viral vehicles. Immunogenicity is a major concern for AAV delivery. Even if immunogenicity is avoided in single administrations of the treatment, repeated administrations increase the risk of aberrantly triggering the immune system. However, the main challenge with AAV delivery is the stability of the RNA payload.

“Lipid nanoparticles are the main players in nonviral technologies for RNA therapeutics. They did a great job for RNA vaccines,” says Suzanne Saffie-Siebert, PhD, CEO of SiSaf, an RNA delivery and therapeutics company. “However, AAV capsids consist of a protein shell which isn’t robust enough during in vivo applications as it is prone to enzymatic degradation. As a result, AAV capsids are highly susceptible to rupture, releasing the payload before reaching their target.”

Although LNPs can be formulated to encapsulate high payloads, instability of the lipid bilayer in LNPs can cause them to rupture during storage or in vivo upon interactions with serum proteins, and prematurely release their cargo.

Stability and storage

Delivery issues with LNPs arise when moving beyond RNA vaccines into the growing field of RNA therapeutics that require specific targeting approaches and enhanced durability.

“Beyond vaccines, you need a delivery system that offers proper targeting and is able to stay in the system long enough to reach the selected cells,” says Saffie-Siebert. “Stability is the main problem with LNPs, which results in follow-up problems.”

When the delivery system is not stable enough to hold its therapeutic RNA cargo till it reaches the target in sufficient abundance, one must either increase the dosage or administer the treatment repeatedly, which reduces safety and increases cost. Repeated injections create immunogenicity issues for LNPs, particularly pegylated lipid compositions, as they do for viral particles.

Moreover, the use of ultra-cold -80°C or -20°C freezers to store RNA-containing LNPs is perhaps not a huge challenge for western countries, but it is not feasible for financially challenged parts of the world.

“You cannot have a global product that requires ultra-cold storage. Even for RNA vaccines, it is a challenge,” says Saffie-Siebert. “If RNA therapeutics are to become the next revolution in medicine, you need better and more sophisticated delivery systems.”

A hybrid solution

Silicon increases the stability of the hybrid delivery system compared to LNP, thereby enhancing the durability of the drug in circulation. [Suzanne Saffie-Siebert]
When Saffie-Siebert graduated from the University of London in 1998, she had been working on plasmid-based DNA gene therapy delivered by lipid particles. RNA had not yet taken center stage in therapeutics. DNA was the frontier for gene therapy.

“Even then we knew lipid delivery was limited. But I stayed in the field of organic materials, lipids and polymers, until 2000. Then I expanded into inorganic materials including silicon. The SiSaf RNA delivery technology is a combination of my academic and industrial experience,” says Saffie-Siebert. “The hybrid inorganic silicon and organic lipid vesicle is the solution for the current shortcomings of LNPs.”

The enhanced stability of the hybrid system compared to LNP increases the durability of the drug in circulation. This enables the drug to reach endosomal compartments and stay long enough to knock down genes of interest for a therapeutic effect. SiSaf’s silicon-stabilized hybrid lipid nanoparticles (sshLNP) are effective for extended periods compared to LNPs, enabling easy transport worldwide.

“We have a series of data that shows no reduction of effect of the RNA drug in the hybrid delivery system after two weeks at 37°C. RNA is still intact. It performs as well as the fresh product,” says Saffie-Siebert.

Moreover, the sshLNP technology, which the company calls Bio-Courier, does not use any immunogenic material. “Silicon is safe to use and lipid has no immunogenicity.” The technology does not use cholesterol, and only small quantities of pegylated lipids are used if needed. Both in vitro and in vivo data shows the complete lack of any immunogenic or toxic effect due to the delivery technology in any cell line tested by SiSaf thus far.

Saffie-Siebert said, “Although the Bio-Courier carrier system is an innovative new arrival, we believe it is safe and shows promise.”

Underlying chemistry

The silicon-lipid hybrid system includes silicon inside, outside, and in between the lipid bilayer.

“We call it an intel-inside-intel-outside system. Silicon binds and holds everywhere when it sees lipid particles. The layer of silicon inside and outside the lipid bilayer controls the motion of lipid molecules in the lipid bilayer,” says Saffie-Siebert.

Organic vesicles such as LNPs face a fundamental problem: they rupture. The silicon scaffold matrix lends stability to the vesicles. The hybrid system combines the best of both worlds—the safety of the organic world and the stability of the inorganic world.

Silicon controls the release of the cargo. Once silicon starts dissociating from the system in solution, RNA is released.

“Instead of fusion, you’re now talking about solution. Through controlled release, the system offers better protection,” explains Saffie-Siebert.

Unlike a water-filled balloon that spills its contents easily, silicon can be likened to a net over the balloon and a scaffold within, providing control over the eventual release of the contents.

“Sisaf’s Bio-Courier addresses the issues of LNPs by stabilization via silicon nanoparticles (SiNPs) that occupy the aqueous core and lipid bilayer via an array of noncovalent interactions and, in turn, stabilize the lipid bilayer. Bio-Courier can sustain serum protein interaction without rupturing. This significantly minimizes drug release, offering high RNA payloads,” says Saffie-Siebert.

Accoutrements of assembly

RNA therapeutics that are being currently developed for delivery through LNPs involve the introduction of RNA into the lipid particles during the vesicle production process. This approach poses two problems. First, when RNA is introduced into the LNPs during the production process, it is susceptible to degradation. Secondly, RNA encapsulated in LNPs must be transported under specific storage conditions that may include ultracold temperatures.

“The beauty of Bio-Courier is that we do not introduce the RNA into the hybrid particles during the manufacturing process of the delivery system,” says Saffie-Siebert. “The vesicles are made as empty carriers. The RNA is introduced once the carriers are fully formed. That’s a massive advantage.”

The benefit of this approach is obvious: one can send the empty carrier to destinations worldwide without any storage temperature restrictions. Once the RNA cargo and the hybrid delivery system reach their destination, they are combined through a simple assembly process.

“Because the hybrid delivery vesicles generate a massive electrostatic shield and RNA is negatively charged, when you mix the two oppositely charged particles, RNA condenses and is included in the vesicles,” says Saffie-Siebert. “It’s a straightforward process and does not require any external pharmaceutical instrument or process.”


Drug delivery to the eye is a challenge. Using live imaging, Saffie-Siebert’s team has demonstrated the uptake of fluorescent siRNA by corneal epithelial cells in vitro and in animal models, using the novel delivery system.3 Sisaf has now partnered with Avellino to use its technology for the development of an siRNA-based local treatment for corneal dystrophy (SIS-201-CD).

“For the first time, we’re able to use eyedrops instead of injections into the eye to administer the RNA therapeutic,” says Saffie-Siebert.

Sisaf’s novel technology is also being used to develop an siRNA-based treatment for osteopetrosis—a rare pediatric bone disease with no available treatment. The therapeutic (SIS-101-ADO) that suppresses the expression of CLCN7 is administered systemically. Animal model studies conducted thus far show a clear achievement of the primary endpoint of the disease, which involves clearing of debris in the bone tissue. The project is currently at the stage of IND application.

“We did head-to-head comparisons between LNP and Bio-Courier delivery and show Bio-Courier makes or breaks the osteopetrosis siRNA therapeutic effect,” says Saffie-Siebert.

Sisaf’s Bio-Courier carrier system has been approved by MHRA, the U.K.’s equivalent of the FDA, and the company is gearing up for FDA approval. Saffie-Siebert strongly believes the future is all about precision medicine and tailor-made delivery systems. She speculates that the Bio-Courier system will refine progressively through several generations, replacing the pioneering success of LNPs for the delivery of RNA therapeutics. Over the next decade, Saffie-Siebert expects to see the company’s new delivery system being used to deliver drugs for specific diseases to target organs, including the brain.


  1. Kazi KM, Mandal AS, Biswas N, Guha A, Chatterjee S, Behera M, Kuotsu K. Niosome: A future of targeted drug delivery systems. J Adv Pharm Technol Res. 2010 Oct;1(4):374-80. doi: 10.4103/0110-5558.76435. PMID: 22247876; PMCID: PMC3255404.
  2. Labouta HI, Langer R, Cullis PR, Merkel OM, Prausnitz MR, Gomaa Y, Nogueira SS, Kumeria T. Role of drug delivery technologies in the success of COVID-19 vaccines: a perspective. Drug Deliv Transl Res. 2022 Nov;12(11):2581-2588. doi: 10.1007/s13346-022-01146-1. Epub 2022 Mar 15. PMID: 35290656; PMCID: PMC8923087.
  3. Baran-Rachwalska P, Saffie-Siebert S, Moore CBT. Delivery of siRNA to the Eye: Protocol for a Feasibility Study to Assess Novel Delivery System for Topical Delivery of siRNA Therapeutics to the Ocular Surface. Methods Mol Biol. 2021;2282:443-453. doi: 10.1007/978-1-0716-1298-9_24. PMID: 33928589.
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