From Formulation to Framework: Regulatory Paths for Nanomedicines

The evolving regulatory landscape & what decelopers need to know.  

Why this matters. For nucleic acid therapeutics, especially those using lipid nanoparticles (LNPs), the interplay between chemistry, formulation, and biological performance is complex. Regulatory expectations around safety, efficacy, and quality must account for this complexity and recent efforts from agencies like the EMA and FDA aim to do just that.

New Era, New Rules. With the approval of LNP platforms for siRNA (Onpattro®), mRNA vaccines (Comirnaty®, Spikevax®), and more candidates in the pipeline, regulatory science is racing to catch up with the innovations. Emerging tools and mechanisms (like the FDA’s new “Plausible Mechanism” pathway) could accelerate access to RNA-LNP therapies for rare diseases.

Nanomedicine meets regulation: The current landscape

Regulatory agencies have historically used broad terms like “complex drugs” or “advanced therapy medicinal products” (ATMPs), which don’t fully capture the nuances of nanomedicine, particularly those involving multi-component systems like LNPs. Despite widespread use, the term nanomedicine lacks a globally harmonized definition. Regulatory agencies define nanomedicines either by particle size (typically 1–100 nm) or functional criteria such as novel properties that emerge at the nanoscale (e.g., controlled release, selective targeting). In 2025, nano-enabled products are assessed under existing medicines frameworks – but whenever nanoscale properties affect exposure, safety or performance, regulators expect deeper characterization and justification.

The FDA does not have a separate nanomedicine pathway but provides guidance through product class-specific frameworks. The EMA has included nanoparticle-containing medicines under the Committee for Advanced Therapies (CAT) but lacks unified nanomedicine criteria. In its recent report, The EMA Horizon Scanning Report on Nanotechnology-Based Medicinal Products (2025) formally identifies nanotechnology as one of the emerging and converging technologies requiring proactive regulatory approaches, due to increasing complexity, novel materials, and delivery pathways that challenge current assessment tools.

For nanomedicine developers, the practical challenge is not memorizing every guideline, but recognizing whether a program’s data package, rationale and assays are consistent with how EMA, FDA and the broader regulatory-science community evaluate nano-specific behaviors, or whether key expectations are missing. The lack of a unified framework is particularly challenging for developers of LNP-based mRNA therapies, which combine a biological payload (mRNA) with synthetic delivery vehicles. These hybrid products often face case-by-case review, depending on the nature of the carrier, the manufacturing process, and therapeutic class.

Who is actually in charge?

As nanomedicine advanced, key pharmaceutical regulatory authorities introduced specific guidelines for assessing nanomaterials and approved the first drugs incorporating nanostructured carriers and nanoformulations designed to improve efficacy and safety. At present, there is no unified regulatory authority that establishes standardized guidelines specifically for nanomedicines.

Regulators & global harmonization

• FDA uses the guidance “Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology” to trigger additional evaluation when nanoscale features or size-dependent behaviors are present. FDA product-specific guidances offer case-by-case instructions, e.g., for Onpattro®, Comirnaty®, and Spikevax®.

• EMA regulates nano-enabled products in the EU/EEA and has issued several reflection papers (IV iron nano-colloids, coated products, liposomes, block-copolymer micelles). The 2025 Horizon Scanning report lists nanomedicine as a priority foresight area, calling for new methods, stronger modelling frameworks, and earlier scientific advice.

• Regulatory fragmentation slows innovation. In response, international efforts are underway: The International Pharmaceutical Regulators Programme (IPRP) Nanomedicines Working Group promotes regulatory dialogue, though 2025 EMA analysis highlights ongoing global divergence across EMA, FDA, PMDA and WHO. This creates opportunities for RNA-LNP developers to adopt platform-based regulatory strategies supported by consistent guidance across regions.

Influential organizations & standards

• ISO TC 229 & ASTM E56 – terminology and analytical standards frequently referenced in regulatory science.

• NCL / EU-NCL – assay cascades for physicochemical, immune and tox profiling.

• ETPN, Nanosafety consortia, Nanomedicine Regulatory Coalition – support harmonization and strategic alignment.

• In Europe, a Joint EMA-EUnetHTA guideline offers scientific advice for developers of nanomedicines and follow-on versions. In the US, the FDA Nanotechnology Task Force and initiatives like the Emerging Technology Program are relevant for RNA-LNP developers.

FDA’s dual trigger

In response to the challenges, the FDA has developed more nuanced regulatory entry points for nanomedicines. Two primary “triggers, i.e. novel active ingredient or novel delivery system, help determine how much scrutiny a product will receive. A product may require expanded review if:

• It contains nanoscale structures (~1–100 nm)

• It exhibits dimension-dependent behaviors even above 100 nm

If triggered, FDA expects expanded: Characterization, Bioanalytical validation, Mechanistic PK justification, Immunological safety analysis.

Across EMA, FDA and NCL work, there is a clear convergence: nano products must be characterized not only by classical QC tests but by a multi-layered set of physical, structural and biological assays.

The question is: Does the characterization package match that reality, or just tick a few basic boxes? You don’t need to show every method on this list in every project – but a credible program today normally has a clear rationale for which of these boxes are ticked and why.

Check out previous article on critical quality attributes (CQAs) and all the methods here.

Click here to access reflection papers for free: https://docs.google.com/spreadsheets/d/1sIowB2dBslcswBzcXBBi1S9mZKC6lEzv/edit?usp=sharing&ouid=110838120543696752090&rtpof=true&sd=true

Table 1. Core characterization aspects

Chemistry, Manufacturing & Controls (CMC): The foundation for approval

Robust CMC strategies are essential for de-risking nanomedicine, especially RNA-LNP programs. Agencies now expect early alignment on CQAs such as particle size, polydispersity index (PDI), encapsulation efficiency, and surface charge. Advanced analytical techniques (e.g., DLS, cryo-TEM, HPLC) and validated release assays help demonstrate formulation integrity and process consistency. Early-phase CMC investment is often a predictor of regulatory success and speed.

• EMA’s reflection papers emphasize:

• nano-specific CQAs

• validated coating/assembly steps

• raw material consistency

• batch-to-batch reproducibility

• comparability after changes

The 2025 Horizon Scanning report adds the dependency on specialist raw materials, sustainability and environmental considerations, and the need for strong lifecycle-management frameworks.

Regulatory gaps for next-generation nanomedicines

Despite growing regulatory attention, current frameworks still lag behind the complexity of nanomedicines, especially RNA-LNP products. The EMA and other agencies have identified several persistent gaps:

1. Lack of harmonized analytical methods

• EMA notes shortages of:

• validated nano-specific analytical methods

• reference standards for complex nanosystems

• robust comparability tools

• assays with in-vivo relevance

This aligns with long-standing translational challenges such as the absence of a standardized endosomal escape assay, and limited harmonization in dynamic protein corona profiling.

2. Gaps in prediction and modelling tools

EMA stresses the need for:

• better biological prediction models
• validated computational and AI-assisted tools
• stronger PBPK (physiologically based pharmacokinetic) frameworks for nano-constructs

3. Safety and long-term behavior remain unclear

Key uncertainties flagged include:

• immunotoxicity and immune modulation
• long-term biodistribution
• nanoparticle persistence
• chronic exposure risks

4. Manufacturing vulnerabilities

The EMA report discusses:

• supply-chain fragility for specialty materials
• dependence on non-EU manufacturers for enabling nano-technologies
• the need for robust QbD frameworks for nano-enabled constructs
• sustainability considerations — energy, solvents, and complex process steps

5. Global regulatory inconsistency

EMA highlights:

• divergent approaches across EMA, FDA, PMDA, WHO
• lack of shared terminology

6. Intersections with other modalities

Nanomedicine is grouped with:

• mRNA platforms
• advanced formulations
• complex biologics
• ATMPs
• combination products

7. Need for earlier scientific advice

Because of complexity, EMA recommends:

• earlier Scientific Advice procedures
• early dialogue on assay suitability
• justification of nano-specific risks and benefits
• proactive risk management planning

The above indicates that nano-regulation increasingly overlaps with biologics, devices, and RNA therapeutics.

LNP-RNA therapeutics: Why the rules must evolve

Nanomedicines like LNP-RNA therapeutics require more than conventional CMC paradigms. Each LNP component (ionizable lipid, helper lipid, cholesterol, PEG-lipid) can impact pharmacokinetics, immune response, and delivery site. For LNP-RNA drugs, formulation is not just an excipient story - it is the product. The combination of RNA sequence and modifications (e.g., pseudouridine, capping), LNP composition & structure (e.g., solid core vs. liposomal bilayer), and surface chemistry (e.g., PEG type, corona profile) collectively determine how the drug performs. This calls for:

• Multi-parameter CQAs

• Functional bioassays (not just analytical release tests)

• Advanced characterization (e.g., cryo-TEM, MALS, SAXS)

• Batch-to-batch control of self-assembling systems

Implications for developers:

• New LNPs must show evidence of reproducibility, safety, and biodistribution.

• Regulatory agencies now expect multi-site manufacturing data, batch comparability studies, and scalable formulation processes.

• Agencies are also requesting more detailed studies on immune responses, anti-PEG antibodies, and potential for re-dosing.

FDA’s “Plausible Mechanism” Pathway: Enabling faster entry for RNA-LNP drugs in rare diseases

In a major policy update, the FDA recently introduced the “Plausible Mechanism” pathway designed to accelerate development of therapies for rare and ultra-rare diseases, including genetic disorders targeted by LNP-RNA drugs.

What it is: A regulatory framework that allows early-stage therapies to proceed to clinical trials without requiring detailed mechanism-of-action data upfront. The FDA accepts a scientifically “plausible mechanism”, enabling developers to generate supporting evidence during clinical development rather than before IND approval.

Why it matters: RNA therapeutics often work via modulation of gene expression, but their biological effects may be tissue-specific, cell-type-dependent, and hard to prove preclinically. LNP biodistribution and immune interaction are complex, making early Mechanism of Action (MoA) certainty difficult. This pathway acknowledges these complexities and lowers the barrier for entry into clinical development, especially for rare diseases with no existing treatment.

Use case potential: Developers of RNA-LNP therapies for inborn errors of metabolism, rare hematologic disorders, or monogenic immune diseases now have a clearer path forward. Preclinical focus can shift toward pharmacology and safety, while mechanistic validation can follow in parallel with early trials.

Caveats: This is not a lower regulatory standard. Rigorous data will still be required. Sponsors must provide a strong scientific rationale, robust quality systems, and an ability to monitor safety in early-phase studies.

Impact: This change is seen by many as a game changer for biotech innovators working in RNA, mRNA, and gene-editing-based therapies.

Looking ahead: Nanomedicine is gaining regulatory traction

LNP-RNA medicines are redefining what drugs can do, but also how they must be assessed. Nanomedicines are evaluated under existing EMA and FDA medicines frameworks, but class-specific reflection papers, cross-cutting nanotechnology guidance, standardized characterization/hemocompatibility protocols (ISO/ASTM/NCL), and EMA’s 2025 horizon-scanning priorities all point in the same direction: nano-specific properties must be understood and justified rather than treated as a black box. Every product is still judged case-by-case, which makes the quality of the data package, not the label “nano”, the real differentiator.

As regulators catch up to science, forward-looking frameworks like the FDA’s Plausible Mechanism pathway and IPRP guidance on nanomedicines give developers more clarity and flexibility. Looking ahead, harmonizing LNP-specific guidance across global agencies will be key to scaling these therapies to more patients, faster. One promising shift in regulatory science is the move toward platform-based assessments. Rather than evaluating each mRNA-LNP therapy de novo, regulators are exploring how prior data from similar constructs, e.g., changes in payload with consistent delivery platform, can streamline review. This is especially relevant for vaccines and therapeutics using the same ionizable lipid and formulation process.

In the meantime, early dialogue with regulators, strong preclinical data packages, and robust quality controls will remain the pillars of successful development. To keep this usable, here is a filter you can apply in minutes:

The checklist with four concrete questions

1. Which EMA/FDA documents does the team explicitly work to? If IV iron, coated products or liposomes are involved and nobody mentions the relevant reflection paper or FDA nano guidance, that’s a yellow flag.
2. Is the characterization cascade coherent? Do you see a clear story from size/morphology through surface/corona to hemocompatibility and immune readouts – or just scattered tests?
3. Is there credible process control? Can they explain CQAs for the nano part and how manufacturing keeps them in range?
4. Are standards and NCL-style protocols referenced? You don’t need a wall of ISO numbers – but some alignment with ISO 80004 vocabulary, ISO 22412 DLS principles, ASTM E2524 hemolysis, and NCL protocols is a good sign.

Download the full article here.

Written by

Dr. Dominik Witzigmann 

Dominik is an entrepreneurial scientist with deep expertise in nanomedicines and nucleic acid delivery. In 2024, he was named Highly Cited Researcher, recognizing him among the world’s most influential researchers in the field. Dominik obtained his Ph.D. in Pharmaceutical Technology from the University of Basel in Switzerland, and held research positions at leading institutions including University College London (safety/tox), German Cancer Research Center (RNAi & cancer), University of Basel (targeted nanomedicines & DNA delivery) and the University of Zurich (mRNA-based genome editing). To focus on extrahepatic RNA delivery, he later joined the team of Prof. Pieter Cullis at the University of British Columbia. Dominik has held leadership roles in Canada’s NanoMedicines Innovation Network (NMIN) and served on the Board of the CRS Gene Delivery and Genome Editing Focus Group. To translate next-generation LNP technologies into the clinic, Dominik co-founded and leads the LNP-nucleic acid company NanoVation Therapeutics. 

Dr. Jayesh Kulkarni

Dr. Kulkarni obtained his PhD from the University of British Columbia and has over 15 years experience in the nanoparticle drug delivery field. He has published over 40 peer-reviewed articles and is a co-inventor on numerous patents. Dr. Kulkarni’s research has focused on the role of the various lipid components in LNP and the biophysics that governs particle formation. His work has contributed to clinical translation, including scale-up and manufacturing of LNP systems in accordance with GLP and GMP regulations. Dr. Kulkarni is a leader in the design and development of lipid nanoparticle (LNP) formulations of small molecule and nucleic acid therapeutics. He currently serves as the Chief Scientific Officer of NanoVation Therapeutics, an LNP-RNA formulation developer.

Ana Petkovic, PharmD, spec QP

Ana is Regulatory Affairs Specialist at AstraZeneca for almost 7 years, in Serbia. She is a pharmacist, holds Master of Science (MSc) in Pharmacy from the Faculty of Pharmacy, University of Belgrade and finished academic QP Specialization at the same University. She is an experienced pharmacist in regulatory field - preparation of documentation for Marketing Authorization application, Licence renewal application, variation application and all relevant submissions to Drug Agency and Ministry of Health as well as monitoring of the process until the issuance of approval letter by the Agency for Medicines and Medical devices. She is proud to work for a company like AstraZeneca, because has the opportunity to learn about innovative medicines in Oncology, CVRM, Respiratory & Immunology, Vaccine & Immunology (as was COVID 19 Vaccine). Also worked in the retail industry – pharmacy. As lifelong student wants to expand her skills and knowledge in theory and in practice in regulatory field. She is happy to learn new things and wants to monitor regulations on wider lever, having in mind, that Serbia is EU accessing country. She also wants to contribute to regulatory affairs and quality fields to put the patients on the top and secure that the patient receives the appropriate medicine always.

Dr. Marija Petrovic 

Marija is a pharmacist with a PhD in Biopharmacy from the University of Geneva, and a cancer research (ISREC)–trained professional through EPFL, with over seven years of experience in nanomedicine. During her PhD, she worked on miRNA and STING ligand nanocomplexes for cancer immunotherapy, gaining deep expertise in nanoparticle characterization and translational workflows. Certified by the EU-NCL in nanobiotechnology and awarded by Innosuisse (Swiss Innovation Agency) with two prizes (jury and public) for the best life science project, she also earned support from FONGIT, Geneva’s leading deep-tech incubator. As the founder of NanoSphere and an active contributor to the Controlled Release Society (Communication Chair for the Gene Delivery and Editing Group (GDGE), and Industry representative at Nanomedicine and Nanoscale Delivery (NND)), Marija focuses on making next-gen medicine scientific advances more visible, understandable, and useful to the communities that can turn them into impact.