Make your intracellular drug delivery system work harder – and get to clinic faster.

Design, formulate, characterise and manufacture your nano-delivery systems for multiple payloads and targets with CPI’s state-of-the-art facilities and expertise.

At CPI, we help innovators accelerate the development of advanced drug delivery systems through our cutting-edge nanopharma capabilities. From lipid nanoparticles to polymeric and alternative nanomedicine platforms, we provide end-to-end support from formulation design and high-throughput screening to scale-up and GMP readiness. Our Intracellular Drug Delivery Centre offers access to expert teams, automated technologies and advanced analytical tools to overcome complex drug delivery challenges. Whether you’re developing RNA-based therapeutics, small molecules or biologics, our flexible, collaborative approach can help you design, optimise, and manufacture smarter, more effective nano-delivery solutions.

Blog #1: Navigating Drug Delivery Systems: Key Considerations and New Approaches – Juliana Haggerty, Head of Centre of Excellence, CPI.

Juliana Haggerty, Head of Centre of Excellence, CPI

The development of next-generation therapeutics: RNA vaccines, gene editors, peptides and proteins, has brought remarkable promise to medicine. Yet for many of these modalities, success hinges on more than the active ingredient. Whether these molecules work in vivo often depends on whether they can be protected, targeted, and released at the right site of action.

For large, fragile, or membrane-impermeable molecules, delivery is no simple task. Encapsulation into nanoscale systems—lipid, polymeric, peptide-based, or inorganic—has become a key strategy. These delivery systems are not merely passive carriers; they actively define a therapy’s stability, uptake, biodistribution, and overall performance.

This presents a central challenge: designing and optimising nanoparticle systems requires both scientific precision and a deep understanding of biological systems. While encapsulation can help overcome many of the inherent limitations of RNA and other large molecules, it also introduces layers of complexity that must be fully understood, controlled, and translated into scalable processes.

Scientific, Manufacturing, and Regulatory Challenges in Nanoparticle Drug Delivery

Delivering RNA, protein, and peptide therapeutics to intracellular targets involves navigating multiple interconnected barriers. While nanoscale carriers offer elegant solutions, they also introduce complexity across both scientific and translational dimensions.

Stability and Intracellular Delivery

Biological payloads are inherently unstable in systemic circulation, where enzymatic and oxidative degradation can rapidly inactivate them. Encapsulation can offer protection, but the stability of the final formulation depends on nanoparticle composition, surface properties, and excipient interactions.

Once internalised, nanoparticles often face another barrier: endosomal entrapment. Without effective endosomal escape mechanisms, the therapeutic cargo may never reach the cytoplasm. Even subtle formulation changes—such as adjusting lipid tail length or polymer charge—can significantly impact delivery efficiency, underscoring the need for systematic optimisation early in development.

Targeting and Safety Considerations

Achieving delivery beyond the liver remains a major challenge. Many nanoparticles, especially LNPs, accumulate in hepatic tissues due to passive uptake. For applications requiring delivery to tumours, muscle, immune cells, or the central nervous system, rationally designed targeting ligands or alternate materials are needed.

At the same time, immunogenicity remains a concern. Nanoparticles, particularly those carrying nucleic acids, can trigger innate immune responses, including cytokine release and complement activation. Understanding how particle size, charge, and composition influence these outcomes is essential to developing safe, effective formulations.

From Bench to Clinic: The Manufacturing Challenge

Even when a nanoparticle performs well in early studies, scaling up for clinical or commercial use poses new hurdles. Lipid and polymeric systems are highly sensitive to shear rates, mixing regimes, and solvent dynamics. What works at the bench may not be easily transferred to GMP settings.

Robust process development encompassing mixing, buffer exchange, solvent removal, and lyophilisation is essential to maintain product quality at scale. Continuous manufacturing and real-time monitoring can enhance consistency, but a thorough understanding of critical process parameters is the real key to success.

Regulatory Landscape and Precedent

The regulatory acceptability of a delivery system can influence both timelines and risk. Platforms with precedent—such as PEGylated liposomes or well-characterised polymers—may follow a more established path to approval. Novel materials or constructs, however, often require bespoke toxicology and immunogenicity studies.

Lipid nanoparticles were first approved in 2018 for siRNA delivery in Onpattro® (patisiran). Their rapid adoption in mRNA vaccines during the COVID-19 pandemic expanded regulatory acceptance, setting a useful precedent for future RNA–LNP programmes. Nevertheless, new or modified formulations still require rigorous, data-driven safety and efficacy evaluation.

Encapsulation Platforms: From LNPs to Polymers and Beyond

Several classes of nanocarriers are in active use or development, each offering distinct advantages depending on the payload and therapeutic goal.

• Lipid nanoparticles (LNPs): Clinically validated through multiple mRNA vaccines, LNPs offer efficient encapsulation, endosomal escape, and modular tunability (size, charge, PEGylation). However, they predominantly target the liver, although there is significant research activity into extrahepatic delivery and targeting.

• Polymeric nanoparticles: Platforms based on PLGA and related polymers support sustained release, pH-responsive delivery, and surface functionalisation. These can be well suited to small molecules, peptides, and protein payloads.

• Peptide-based systems: Offering programmable membrane interactions and receptor targeting, peptides show potential for intracellular protein delivery and precise tissue targeting.

• Inorganic nanoparticles: Although less common in approved therapeutics, materials like gold or silica offer stable encapsulation and multifunctional potential, including diagnostics and combination therapies.

These platforms are not interchangeable. Success relies on matching the delivery system to the therapeutic context—and validating this fit through carefully designed in vitro and in vivo studies.

Linking Formulation to Function: The Need for Integrated Tools

Given the complexity of nanoparticle design, formulation development now demands integrated, data-rich approaches.

High-throughput screening, coupled with multiparameter characterisation and biological assays, is essential to understand how formulation choices affect performance—such as cellular uptake, gene expression, biodistribution, and toxicity.

Design-of-experiment (DoE) approaches, paired with robust analytics, are enabling teams to ask:

• Which formulations yield stable, scalable products?

• Which reach the right cells and release their cargo efficiently?

• Do they avoid unwanted immune activation?

• Which in vitro assays best predict in vivo success?

Answering these questions with confidence is key to reducing development risk and accelerating timelines.

Bridging the Gap: The Role of the Intracellular Drug Delivery Centre

To support companies tackling these challenges, the Intracellular Drug Delivery Centre has been established in the UK - a national platform combining infrastructure, expertise, and collaborative workflows for nanoparticle development and scale-up.

Led by CPI in partnership with Imperial College London, University of Liverpool, University of Strathclyde, and the Medicines Discovery Catapult, the Centre provides:

• High-throughput formulation screening: Automated systems for testing thousands of nanoparticle designs against key performance metrics.

• Comprehensive characterisation: From particle size and encapsulation efficiency to RNA integrity, immunogenicity, and in vivo performance.

• Iterative in vitro testing: Validated assays to assess cellular uptake, expression efficiency, and innate immune responses.

• Process development and manufacturing: Scale-down and scale-up support across multiple mixing and purification approaches, delivering GMP-ready processes.

Importantly, the Centre is structured for open collaboration enabling early-stage companies, spinouts and SMEs to access cutting-edge tools and expertise.

CPI’s Broader Capabilities in RNA Therapeutics

The Intracellular Drug Delivery Centre forms part of CPI’s wider investment in enabling RNA-based medicines. CPI was the first organisation in the UK to manufacture both an RNA drug substance and its encapsulating LNP at clinical scale. Our integrated offering includes RNA and formulation development, platform manufacturing processes, advanced analytics, and scalable GMP manufacturing—all within one setting.

We also support oligonucleotide development and synthesis, providing end-to-end capabilities that bridge research, development, and commercial readiness for emerging RNA therapeutics.

Conclusion

Drug delivery is no longer a secondary consideration, it’s a central determinant of therapeutic success. For complex, intracellularly active molecules, encapsulation technologies provide a pathway past biological barriers. But they must be designed with precision, characterised in detail and translated into robust manufacturing processes.

By supporting this entire journey from formulation through to GMP manufacturing, the Intracellular Drug Delivery Centre is helping the next generation of medicines reach patients faster, safer and with greater confidence.

Blog #2: Overcoming intracellular drug delivery barriers with LNP technology – Nga Vo, Senior Research Scientist, CPI.

Overcoming intracellular drug delivery barriers with LNP technology

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 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, they can lower material use, reduce waste, and cut operational costs.

Stability and cold chain burdens

RNA molecules encapsulated in LNPs are intrinsically unstable, 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) - 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.

We support analytical method development, validation, and QC transfer to help maintain reproducibility. Using process analytical technology (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 reproducbility 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 process analytical technologies (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, high-throughput automation and encapsulation platforms enable rapid screening and optimisation, expediting new product development and enhancement.

Additionally, CPI’s purification expertise, utilising 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, driving 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.

Theraphix case study – video

Developed by RNAssist with support from CPI, and funding from Innovate UK, this groundbreaking RNA stabiliser uses deep eutectic solvents (DES) to maintain vaccine stability and efficacy at ambient temperatures. This innovation streamlines logistics, reduces costs, and ensures vaccines can reach even the most remote and underserved communities. With the support of CPI’s state-of-the-art facilities and expert scientists, RNAssist was able to optimise the encapsulation and stability of Deep Eutectic Solvents (DES) in lipid nanoparticles (LNPs). Our team also demonstrated the large-scale manufacturability of TheraPHIX™, paving the way for solutions that could transform vaccine equity and global access. In this video, hear from RNAssist’s CEO Andy Goldsborough and CPI’s Senior Research Scientist Nga Vo about the journey to develop TheraPHIX™, and the future of global vaccine distribution.

Regulatory requirements for nanotechnology-based RNA vaccines and therapeutics: a quick start guide.

This quick-start guide, developed by the team behind the Intracellular Drug Delivery Centre, provides a comprehensive roadmap to navigating the complex regulatory pathways for nanotechnology-based RNA vaccines and therapeutics, addressing the need for clear regulatory and quality data requirements. It also includes a decision tree, created by the MHRA, to help innovators understand relevant guidance documents and access support for bespoke interpretation.

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Theraphix case study

Discover how CPI helped RNAssist develop TheraPHIX™, a breakthrough drug delivery solution that stabilises RNA vaccines at room temperature, removing the need for ultra-cold storage. By improving the stability and delivery of lipid nanoparticles, this innovation could transform global vaccine access, reaching remote communities and advancing vaccine equity worldwide.

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