Navigating drug delivery systems: Key considerations and new approaches

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 as 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 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.