Blog 25 Jul 2025 

Overcoming intracellular drug delivery barriers with LNP technology

Explore how LNP innovations are overcoming delivery barriers to unlock the full potential of mRNA and gene-editing therapies.

Juliana Haggerty

Juliana Haggerty

Head of Intracellular Drug Delivery Centre

Lipid nanoparticle (LNP) technology has revolutionised intracellular delivery, enabling breakthrough applications from mRNA vaccines to gene-editing therapeutics. However, innovators working with LNPs still encounter substantial challenges, especially when targeting tissues beyond the liver. Overcoming these barriers is crucial for realising the full potential of nucleic acid therapies. This blog examines the key obstacles in intracellular drug delivery and demonstrates how cutting-edge LNP innovations, combined with strategic support, can help innovators navigate these challenges.

Targeted delivery: moving beyond the liver

Most clinically approved LNP-based therapies, including Onpattro® — a drug consisting of small interfering RNA encased in lipid nanoparticles — and COVID-19 vaccines, naturally accumulate in liver cells due to their inherent hepatotropic nature. Delivering therapeutics to extrahepatic tissues presents a major challenge that innovators typically address through active or passive targeting strategies. Active targeting uses specific ligands grafted onto LNP surfaces to bind receptors on target cells, but this approach increases formulation complexity, can compromise stability, and requires precise ligand conjugation to prevent immune clearance. 

Passive targeting strategies involve adjusting the size, charge, and lipid makeup of LNPs. These changes influence how proteins in the bloodstream interact with and attach to the particles, creating a natural coating called the biomolecular corona. This corona can help guide LNPs to specific tissues, but achieving consistent results remains a challenge. Innovators could overcome this by combining rational design and analytical characterisation, enabling developers to move beyond liver tropism and into broad tissue targeting. 

Scaling up production: bridging the lab-to-market gap

Scaling LNP manufacturing from bench to commercial scale presents substantial hurdles. According to the recent Future of mRNA Report’, 67% of senior biotech leaders identified manufacturing complexity and scalability as significant barriers to mRNA adoption. Robust manufacture and scale-up of these drug products requires precise control of critical quality attributes necessary for optimal clinical performance. This can limit the safety and effectiveness of these systems and result in failure of these products to deliver necessary health outcomes in clinical trials. 

High-throughput encapsulation methods, advanced mixing technologies and automation are essential for scaling up LNP production. Yet, innovators frequently encounter difficulties maintaining uniformity, particle size consistency and encapsulation efficiency at larger scales. Additionally, the transition from lab-scale batches to GMP-compliant production involves extensive validation and method qualification, adding further complexity. 

Using a full pilot‑line design, enables companies to use process analytical technology (PAT)-enabled systems to monitor key process parameters. At CPI, we demonstrated this with a successful project supporting the clinical development and commercialisation of emerging nanotherapeutic drug products by successfully translating academic formulations into reproducible, scalable processes. 

High-value raw materials: managing cost and supply chain risks

Production costs for RNA-LNPs are inherently high due to reliance on specialised raw materials like ionisable lipids. These materials are often available from a limited number of global suppliers, creating bottlenecks and supply chain vulnerabilities and dependence on specialised suppliers poses significant risks, particularly in times of high demand. The constraints of sourcing GMP-grade materials further compound these challenges, inflating costs and complicating timelines for innovators. 

Navigating these supply chain dynamics requires strategic planning, robust risk mitigation strategies, and alternative sourcing approaches to maintain stability and sustainability. Leveraging digital twin technologies help innovators minimise experimental runs by optimising formulation and manufacturing processes digitally, meaning they can lower material use, reduce waste, and cut operational costs. 

Stability and cold chain burdens

RNA molecules encapsulated in LNPs are intrinsically unstable and susceptible to rapid degradation, necessitating stringent storage conditions, often ultra-cold temperatures of ‑20°C to ‑80°C. This requirement significantly complicates global distribution, especially in regions lacking sophisticated cold chain infrastructure, increasing logistical complexity and costs. 

Innovators must continually explore formulation strategies to enhance thermostability, including optimising lipid composition, employing novel excipients, or refining encapsulation processes to mitigate cold chain dependence. We partnered with RNAssist, supported by Innovate UK, to tackle this challenge by creating a thermostable solution called TheraPHIX™. We developed a process that demonstrated encapsulation success for multiple deep eutectic solvents (DES), which are non-aqueous, non-organic solid solvents that form a compound liquid when mixed. This enables RNA-LNP vaccines to be stored and transported at ambient temperatures. 

Complex IP landscape

The LNP space is densely populated with overlapping patents covering various aspects from lipid chemistries and manufacturing processes to delivery technologies. Innovators must navigate this complex intellectual property landscape carefully to secure freedom to operate and reduce infringement risks. This requires meticulous patent monitoring and often strategic collaborations or licensing agreements. Early patent landscaping is critical.

Maintaining product quality at scale

Ensuring consistent product quality, safety, and efficacy during scale-up is essential but often difficult to achieve. Reliable analytical methods are critical for verifying key attributes such as purity, potency, and particle characteristics. By developing and qualifying detailed analytical protocols early, innovators can ensure measurement accuracy and build a solid foundation for process control. Implementing robust, PAT-enabled control strategies and quality control (QC) methods allows for real-time monitoring, reduces batch variability, and supports the delivery of high-quality products at scale. 

At CPI, we support analytical method development, validation, and QC transfer to help maintain reproducibility. Using PAT and digital twin approaches, variability in the R&D and scale-up phases can be monitored and improved by allowing innovators to predict and control variability without needing as many physical experiments. It is important for innovators to integrate CMC principles early in R&D, to develop thorough process understanding to ensure reproducibility and product quality consistency. 

Accelerating innovation: our strategic support

Recognising these widespread challenges, CPI has established comprehensive capabilities specifically designed to support innovators in overcoming intracellular delivery barriers. 

We offer specialised expertise in analytical development, including particle sizing, charge analysis, microscopy, and advanced chromatography. Our end-to-end pilot lines incorporate PAT to streamline scaling and automation, significantly accelerating development and reducing costs. We have access to a range of off-the-shelf mixers and bespoke mixers, and high-throughput automation and encapsulation platforms enable rapid screening and optimisation, expediting new product development and enhancement. 

Additionally, CPI’s purification expertise, using methods like tangential flow filtration (TFF) ensures high recovery and smooth transitions to GMP production. 

Towards a promising future

Despite these complex barriers, the future of intracellular drug delivery using LNP technology is exceptionally promising. With strategic, collaborative support, innovators can overcome these hurdles, getting novel therapies to market faster and more efficiently. 

CPI remains at the forefront of this journey, committed to supporting biotech and pharma companies of all sizes in navigating challenges and accelerating the delivery of transformative LNP-based therapies. 

To explore how CPI can support your intracellular drug delivery challenges, please get in touch for a conversation with one of our experts. 

For more information

Juliana Haggerty

Juliana Haggerty

Head of Intracellular Drug Delivery Centre

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