The future of targeted therapeutics with next-gen silica nanoparticle delivery

Nigel Theobald, CEO, N4 Pharma explores the future of targeted therapeutics with next-generation silica nanoparticle delivery.

In the evolving landscape of precision medicine and targeted therapy, success is increasingly determined not only by the efficacy of the drug itself, but also on the precision and reliability of the delivery mechanism employed. Targeted therapeutics, designed to interact with specific cellular pathways or disease sites, necessitate delivery systems that can evade the natural defences and barriers within the body to reach their intended targets without eliciting adverse effects. 

The demand for delivery technologies that can safely, precisely and efficiently transport RNA therapeutics is growing, though current delivery platforms have limitations that make them fall short.  

Advancements in nanotechnology have introduced mesoporous silica nanoparticles (MSNs) as promising candidates for nucleic acid drug delivery applications.  

Current RNA delivery systems  

LNPs and viral vectors are widely used across pharmaceutical and biotechnology, playing a central role in enabling advanced therapeutic development. LNPs have become the industry-standard approach, particularly following their success as the delivery technology for messenger ribonucleic acid (mRNA)-based COVID-19 vaccines. They are capable of encapsulating genetic material, including mRNA, as well as a wide range of biologically active compounds, allowing for controlled delivery to target cells or organs. Their ability to protect nucleic acids during systemic circulation has been clinically validated, proving them in a variety of injectable nanomedicine applications.  

However, the development of LNPs remains complex and technically demanding. Formulations require precise control over composition, preparation, and characterisation to ensure consistence and efficacy. Furthermore, LNPs have a strong tendency to accumulate in the liver, which can limit their utility for extrahepatic delivery. A lack of viable available alternatives has compelled developers to invest heavily in engineering LNPs for broader applications despite these limitations.  

While LNPs tend to dominate the headlines, viral vectors remain another well-established delivery vehicle, particularly in gene therapy. Engineered viruses, such as adeno-associated viruses (AAVs), lentiviruses (LVs), and adenoviruses (AdVs), are modified to deliver therapeutic genetic payloads. These vectors offer high transduction efficiency, often integrating into host genomes for stable, long-term expression of therapeutic genes. Tissue-specific targeting can be engineered to improve delivery precision and minimise off-target effects and in some cases, their ability to activate the immune system can be therapeutically advantageous, such as in oncology applications. Despite their efficacy however, challenges remain with immune responses, limited payload capacity, and manufacturing complexity. 

Creating a new opportunity for nucleic acid delivery  

While LNPs and viral vectors have proved important in enabling breakthroughs like mRNA vaccines and gene therapies, significant hurdles restrict their broader clinical potential. Enter silica-based nanoparticles. Silica is a well-known substance that has been widely used in clinical applications. In the body, silica nanoparticles degrade slowly to nontoxic by-products that are safely passed out of the system. 

Mesoporous silica nanoparticles (MSNs) are hollow particles that, when the surface is appropriately modified, can be used to trap a wide range of molecules with varying chemistries, offering strong biocompatibility and chemical stability. They have been applied in many successful drug formulations already. Recent developments make it possible for MSNs to be re-engineered to bind oligonucleotides of varying sizes, including DNA, RNA and SiRNA, to the functionalised surface of the particle (see Figure 1). By altering its topography, researchers can demonstrate how these particles can become a viable delivery system for nucleic acids and an alternative, effective, non-lipid delivery solution that protects the nucleic acid, delivers enough of it into the cell to trigger the required immune response, while ensuring safety and immunogenicity.  

Overcoming the core challenges of delivery  

Despite major advances in RNA therapeutic design, effective drug delivery remains a central bottleneck in translating innovation into clinical success. Four key challenges continue to define the limitations and opportunities in the field: targeting precision, payload versatility, safety and tolerability, and scalable manufacturing. Comparing LNPs and viral vectors with emerging MSNs highlights current challenges.  

1. Effective targeting and versatile administration 

Precision targeting is essential to maximise therapeutic efficacy while minimising off-target effects and systemic toxicity. Viral vectors offer strong tissue and cell targeting due to their evolved biological specificity, but this advantage comes with a high risk of immune activation and limits their administration to injectable routes. LNPs offer only moderate targeting capabilities and are prone to off-target accumulation – especially in the liver. They are also largely restricted to parenteral administration, with no proven pathway for oral delivery. In contrast, MSNs demonstrate controlled uptake with strong targeting while supporting alternative administration routes. Notably, their potential for oral delivery, combined with minimal immune reactivity, offers an expanded therapeutic reach that current options struggle to achieve.  

2. Carrying complex or multiple nucleic acid payloads  

As therapeutic strategies become more sophisticated, there is increasing demand for delivery systems that can accommodate larger or multiple payloads, such as gene editing tools, combination therapies or multi-step treatment regimens. Viral vectors are fundamentally limited by their small carrier capacity and are not well-suited for the simultaneous delivery of multiple therapeutic agents. LNPs face similar constraints, generally optimized for the delivery of single, small molecules like siRNA or mRNA. MSNs, by contrast, offer structural versatility and high internal surface area, allowing for the co-delivery of diverse therapeutic agents. This payload flexibility enhances therapeutic design and adaptability to support more complex and adaptable treatment strategies. 

3. Safety and tolerability  

As targeted therapies extend into chronic and long-term treatment settings, low-toxicity and immune activation are critical. Viral vectors can trigger strong immune responses, often precluding repeat dosing and raising concerns around immunotoxicity. LNPs, though generally well-tolerated, have been associated with systemic inflammatory responses and liver-related side effects in some cases. These reactions can pose significant risks in repeated or high-dose applications. MSNs however, have demonstrated low immunogenicity and minimal cytotoxicity in preclinical models, supporting safer profiles even with repeated administration.  

4. Manufacturing at scale  

For drug delivery technologies to achieve real-world impact, they must be scalable, cost-effective and compatible with large-scale production. Viral vectors are complex to manufacture, relying on biologically intensive, cell-based systems that are both costly and difficult to scale consistently. LNPs require precision engineering and specialised equipment, which can constrain throughput and add cost. In contrast, MSNs are synthesised using simple, inexpensive manufacturing methods that are well-suited to industrial scale-up. Their ease of production offers clear advantages in cost, consistency and commercial viability, making them attractive candidates for global therapeutic deployment.  

Conclusion  

While LNPs and viral vectors have advanced nucleic acid drug delivery significantly, their limitations are becoming increasingly clear, especially as therapies become more complex. 

MSNs offer a compelling alternative approach. They support the delivery of multiple or complex payloads, enable precise targeting and controlled release, and demonstrate low toxicity and immunogenicity, making them suitable for repeat dosing. Their potential for oral administration and scalable, low-cost production further strengthens their appeal.