From mRNA vaccines to programmable cancer therapies, nanomedicine is redefining how we diagnose and defeat disease - one nanoparticle at a time. For patients, this means more targeted treatments, fewer side effects, and a path toward truly personalized care.

As early as 2015, nanomedicine had already secured over $16 billion in global revenue, supported by steady annual investments of more than $3.8 billion in nanotechnology research and development. While total nanotechnology-enabled product sales across industries surpassed $1 trillion back in 2013, the medical segment has continued to expand at an impressive pace. By 2023, the nanomedicine market alone was valued at $189.55 billion, with forecasts projecting it to surpass $500 billion within the next decade.

„For nanomedicine scientists, this is an exciting era. Nucleic acid payloads (especially longer nucleic acid modalities such as mRNA or circRNA) require an efficient delivery technology - and it is up to us, as a community, to develop innovative solutions that enable safe and effective delivery to the target site” –  Dominik Witzigmann, PhD.

So, what does nanomedicine mean for those new to the field?

Nanomedicine is the application of nano-sized materials to diagnose, deliver, and enhance therapeutics at the molecular level for precision medical use through controlled drug release, targeted therapies (as required for oncology), and medical imaging, including theranostics and tissue engineering. Nanomedicines have been successfully applied in instances such as limiting the toxicity of small molecules (e.g., Abraxane, Doxil), enabling the RNA-based COVID-19 vaccines, and gene editing to correct genetic defects. These technologies deliver therapeutic cargoes directly to specific tissues using nanocarriers designed in a manner that promotes on-target effects and limits off-target “side effects”.  

How are nanomedicines actually made?

There are two main strategies. One approach builds nanoparticles around a drug - using materials like lipids or polymers to encapsulate it through weak, reversible interactions* or via covalent, but biodegradable linkers; This is called the bottom-up method. The other starts with the drug itself and breaks it down into nanosized particles - like nanocrystals – known as the top-down method.

*Hydrogen Bond, Electrostatic or Coulomb Attraction, Metal Ligand Interaction, Van der Waals Interactions, Hydrophilic Interactions, Hydrophobic Interactions

Interestingly, several small-molecule-based nanomedicines on the market today are improved versions of already-approved drugs, just reformulated for better performance; specifically, improving therapeutic benefits and/or overcoming dose-limiting toxicities. Over the last decade, a true game-changer has emerged: lipid nanoparticles (LNPs). These tiny delivery vehicles became globally recognized during the COVID-19 pandemic for their role in carrying mRNA safely and effectively into cells, although they were first used for gene silencing in the liver for treating transthyretin amyloidosis.

Why small (nano) is good?

As particles get smaller, their surface area increases dramatically – often making them more efficient, and often more cost-effective given the increased therapeutic index of the resulting medicine (Figure 1). Think of it like this: a whole effervescent tablet takes time to dissolve, but crush it into powder and it works almost instantly. The same principle applies in nanomedicine. In addition, nanoscale particles can slip through biological barriers such as incomplete vasculature (as in the liver, spleen, or bone marrow), mimic natural cell structures, thereby reducing immunogenicity and prolonging circulation time, and enable precision targeting of disease sites. This not only protects fragile drugs from breaking down in the body but also helps release them exactly where they’re needed, reducing side effects and improving outcomes.

Figure 1 - The total volume is identical in both cases, but the configuration on the left exhibits a significantly greater surface area.

What are the standard definitions in terms of size? Does a 500 nm particle still qualify as “nano”?

Let’s get a bit technical here- it’s worth it, and will help make sense of what comes next.

The European Commission (EC) first adopted a definition of a nanomaterial in 2011 and a final recommendation on the definition of nanomaterial was published on June 14th, 2022.

A nanomaterial is a natural or manufactured material made of solid particles, either individually or in aggregates or agglomerates, where at least 50% of particles (by number) meet one of the following criteria (Figure 2):

(a) 0D - All dimensions (x,y,z) <100 nm (e.g. quantum dots)

(b) 1D - Two dimensions  <1 nm, one >100 nm (e.g. nanotubes)

(c) 2D - One dimension <1 nm, two >100 nm (e.g. nanofilms)

(d) 3D – not considered nanomedicines - all dimensions >100 nm (e.g. bulk powders)

Figure 2 - Dimensional classification of nanomaterials based on shape and size criteria

Therefore, at 500 nm, a particle exceeds the nanoscale threshold and isn’t classified as a nanomedicine. In contrast, a typical LNP used for RNA delivery is around 50–100 nm, well within the ‘nano’ category by EC standards.

Not all nanoparticles created are equal - so what’s the difference?

Nanomedicines are categorized based on their morphology, structure, and composition (Figure 3):

Figure 3 - Comprehensive classification of nanoparticles in nanomedicine: Morphology, Structure, and Composition

1. Morphology

• Nanoparticles: Nano-objects with all three dimensions in the nanoscale; Nanoparticles are not all spheres but may have the shape of needles, extended rods, spring structures,
• Micelles: Self-assembled molecular aggregates, formed above a certain critical concentration in solutions of surface-active agents.
• Nanofibers: One nanoscale dimension; used in drug delivery and wound healing.

2. Structure

• Nanocapsules: nano-object with more than one chemically or structurally distinct wall layer enclosing a hollow or solid core
• Nanocrystals: Solid particles with a periodic lattice of atoms, ions or molecules.
• Nanospheres: Solid spherical particles, often lipid- or polymer-based with embedded drugs.

3.Composition Lipid-based:

• Liposomes: Bi-layered vesicles (mono-, multi-lamellar, polymer-coated) with hydrophilic interior.
• Lipid Nanoparticles (LNPs): Solid core structures, phospholipid coating; biodegradable, high drug loading.

Polymeric-based:

• Polymeric Nanoparticles: Natural/synthetic polymer-based.
• Polymer–Protein Conjugates: e.g., PEG-protein combos for longer circulation.

Protein-based:

• Nab (Nanoparticle albumin-bound)-particles carrying hydrophobic drugs.

Inorganic:

• Colloids: Iron–carbohydrate complexes for iron-deficiency, stable and low-toxicity.

How can we bring nanomedicine from the lab to patients' lives?

Transforming a bold nanomedicine idea into a real-world therapy isn’t a straight line - it’s a rigorous, multi-phase journey. From early screening and rigorous nanoparticle characterization to preclinical lead optimization, large-scale GMP manufacturing, and clinical validation, every step plays a critical role. This process ensures not only the safety and efficacy of nanomedicines but also their readiness to be scaled for global impact.

Who’s the first gatekeeper or sneaky enemy a nanomedicine drug faces on its journey in the blood?

In short, the liver. When drugs are taken orally, they pass through the portal vein to the liver, where they may be broken down before reaching the bloodstream - a process called the first-pass effect. Intravenous (IV) drugs avoid this by entering directly into systemic circulation. However, nanomedicines, even when injected IV, still often accumulate in the liver as the immune system recognizes them as foreign bodies, including clearance by the reticuloendothelial system (RES), particularly by liver resident macrophages called Kupffer cells. This makes the liver a common site for nanoparticle uptake - useful for liver-targeted therapies, but a hurdle when aiming for other organs. LNPs have evolved as highly efficient nanomedicines for nucleic acid delivery to the liver. However, targeting tissues beyond the liver has been challenging due to the rapid systemic clearance. Next-generation platforms, such as the long-circulating LNP (lcLNP™) technology, that enable “de-targeting” of the liver via increased systemic circulation allow accumulation in extrahepatic tissues like bone marrow or tumor sites, reshaping what is possible in systemic RNA delivery.

“Personalized nanomedicine” - but how does a particle know where to go? Let’s take an example of tumor targeting

Let’s start with passive targeting- a strategy built on the Enhanced Permeability and Retention (EPR) effect, first spotlighted by Matsumura & Maeda back in 1986. The idea? Tumors are messy. Their blood vessels are leaky, they’re poorly drained, and they often grow chaotically. This chaos allows nanoparticles to accumulate and stay longer than they would in healthy tissues. But EPR isn’t a one-size-fits-all. Its efficiency varies wildly between tumor types - and even between different lesions in the same patient. In stiff, fibrotic tumors like pancreatic cancer, particles might enter the bloodstream but never make it to the cancer cells. EPR alone just isn’t enough. To push nanoparticles further, researchers have turned to enhancement strategies:

• Physical tricks like ultrasound (sonopermeation), hyperthermia, or radiotherapy to increase permeability.
• Pharmacological priming with agents like TNF, nitric oxide, or fibroblast inhibitors to loosen up the tumor microenvironment.

Still, when more precision is needed, scientists have moved to active targeting. This approach gives nanoparticles a better chance of engaging the target cell - ligands like antibodies, peptides, or small molecules that latch onto specific receptors on tumor cells, blood vessels, or even the extracellular matrix. And while early hopes ran high, some high-profile failures, like BIND-014 and MM-302, reminded the field that smart targeting needs smart patient selection (i.e. patient stratification).

When designing an actively targeted nanomedicine, the first step is simple but critical: decide what you want to target - tumor cells, immune cells, or something else - and design the base nanoparticle in a way that it can actually reach the target tissue for the targeting ligand to bind to the target cell.

The more specific your targeted nanomedicine, the lower the risk of off-target effects. But here’s the catch: the target - like a surface antigen - must be not only present but also abundant and accessible in the patient’s diseased tissue for the therapy to work. Otherwise, even the smartest nanoparticle won’t have much to latch onto. Why does this matter? Clinical trials can fail. The key reason why several targeting-ligand modified nanomedicines have failed, despite promising preclinical data, was the lack of biomarker-driven patient selection. Targeted receptors weren’t consistently expressed across all patients in the clinical trials (in addition to potentially varying EPR). Without identifying and enrolling only those patients whose tumors allowed nanoparticle accumulation as well as expressed the intended target receptors, the therapeutic effect was diluted, leading to underwhelming efficacy results. This highlighted a critical lesson: precision targeting only works when matched with precision diagnostics. More about the benefits and challenges of utilizing active targeting ligands in one of our future articles. In short, the benefits, i.e., therapeutic index, need to significantly outweigh the challenges like complex manufacturing, cost of goods, and storage stability.

Why not turn the tables and target immune cells - arming them to become stronger allies in the fight against cancer?

Targeting immune cells allows us to reprogram the body’s natural defenses to fight cancer more effectively. LNPs can be engineered to deliver mRNA payloads specifically to myeloid & T cells - cells involved in the body’s response to tumors. Once these cells receive the message, they can produce anti-cancer signaling molecules, effectively boosting their tumor-fighting abilities. This strategy holds promise for reaching immune cells that infiltrate tumors, turning them into active agents that recognize and destroy cancer cells from within. We aim to discuss in vivo reprogramming of immune cells for the treatment of cancer and autoimmune disease, utilizing in vivo CAR therapies in an upcoming article. In short, technologies such as the lcLNP™ platform enable efficient and safe delivery of RNA to immune cells, including approaches for in vivo CAR-T reprogramming without the necessity for targeting ligands. Such strategies simplify manufacturing, reduce costs, and improve access to cell-based immunotherapies. More details can be found here.

How nanomedicine is changing rare disease therapy?

Take beta-thalassemia, a rare genetic blood disorder caused by mutations in the HBB gene. Until recently, treatment options were limited to blood transfusions and bone marrow transplants - both risky, lifelong procedures with significant complications. Today, LNP technology allows scientists to deliver gene-editing tools like CRISPR or base editors directly into a patient’s stem cells. These nanoparticles can carry the therapeutic instructions into bone marrow cells, the source of defective blood production - without the need for viral vectors. This kind of in vivo editing could permanently correct the genetic defect with a single, minimally invasive treatment. A few years ago, this level of precision and tissue-specific delivery simply wasn’t possible. Today LNP systems such as the lcLNP™ platform have been tailored for bone marrow targeting and in vivo delivery of gene editing tools – allowing therapies for diseases once considered untreatable. More details can be found here.

What are the key challenges facing nanomedicine today?

Nanomedicines face several distinct categories of challenges. The key is that the development should start with the target product profile (TPP) in mind. Strategic platform design - considering the specific application, payload, disease, manufacturing, and regulatory readiness from the outset - is critical for successful translation. The list of challenges below just outlines the general concepts which need to be considered.

Conceptual Challenges (i.e. disconnect between basic research and clinic)

• Disciplinary Divide: Dominance of chemistry and materials science over clinical translation expertise.
• Excessive Design Focus: Overemphasis on new nanoparticle structures, underexploring clinical relevance and biodistribution behavior.
• Disconnect with Clinical Needs: Lack of robust data on accumulation mechanisms and why most nanomedicines fail in trials.

Safety & Immunological Risks

• Protein Corona: Formation of biomolecular corona alters nanoparticle behavior and biodistribution, complicating targeting and efficacy.
• Organ Toxicity: Potential accumulation in organs like liver, spleen, kidneys necessitates detailed toxicology assessments as well as potential biodegradability studies.
• Thrombosis & Hematology: Thrombosis is the most reported blood related side effect, followed by complement activation and leukocyte issues.
• Immune Interactions: Nanoparticles can cause hypersensitivity via CARPA (Complement Activation-Related Pseudoallergy). Co- or pre-medication to block immune responses and dosing scheme modifications can prevent such effects.
• Species-Specific Effects: Species variability limits the predictability of preclinical models for immune response assessment.

Technical and Industrial Barriers

• Scalability & Manufacturing: Difficulties in upscaling production without losing nanoparticle quality and reproducibility. Issues with batch consistency and control of physicochemical properties like size and charge.
• Characterization: Inadequate standardized methods for nanoparticle analysis, affecting regulatory approvals.
• Regulatory Gaps: No unified guidelines exist yet for nanomedicine product approvals across agencies.

How are regulatory frameworks evolving to keep up with nanomedicine?

Make sure you're aligned with global expectations - review the guidelines and standards from leading regulatory bodies.

What does the future hold for nanomedicine?

Do you want to explore the most relevant publications in nanomedicine since 2024?

How is AI accelerating innovation in nanomedicine?

The potential next era of nanomedicine and RNA therapeutics is being driven by the bold new wave of Artificial Intelligence (AI)/Machine learning (ML) redefining what’s possible in drug delivery - from AI-guided RNA design to ML-based LNP development. Emerging tools in synthetic biology and biological programming are offering new opportunities for designing RNA molecules for controlled expression in target tissues. While numerous efforts are ongoing to adapt such approaches for the design of LNPs, these typically highlight already established principles of formulation design that were identified from previous empirical testing. ML-based strategies require high-quality, systematic training data sets, which currently do not exist in a practical manner to yield fruitful results. High-throughput lipid synthesis and LNP formulation methodologies often compromise on LNP quality and subsequent biological data is further convoluted.  So far, rational design approaches have resulted in clinically proven technologies.

As nanomedicines continue to evolve, translational platforms will be critical in bridging the gap between promising molecular payloads and clinical impact. The next wave of genetic medicines will be defined not only by what we deliver - but where and how we deliver it. 

Coming up next in July: We’re diving into the fascinating world of nucleic acids - from siRNA and mRNA to saRNA, circRNA, DNA vectors, and lncRNAs. Whether it's silencing disease genes or programming protein expression, these molecules are shaping the next generation of precision therapies. Stay tuned - this is where the future of medicine gets personal.

Written by

Dr. Dominik Witzigmann 

Dominik obtained his Ph.D. in Pharmaceutical Technology from the University of Basel in Switzerland. Following research projects at the University College London (toxicity), German Cancer Research Center (RNAi and cancer), University of Basel (targeted nanomedicines and DNA delivery) and the University of Zurich (mRNA-based genome editing), Dominik joined the team of Prof. Pieter Cullis at the University of British Columbia to focus on RNA delivery utilizing lipid nanoparticle (LNP) systems. Dominik had leadership roles within the NanoMedicines Innovation Network (NMIN - a Canadian Networks of Centres of Excellence), he co-founded and led NMIN`s NanoCore to support >30 projects with advanced nucleic acid delivery technologies, and he served as a Board Member of the Controlled Release Society Focus Group “Gene Delivery and Genome Editing”. Dominik has a proven track record in nanomedicines enabling tissue as well as cell specific drug and gene delivery. To translate next-generation LNP technologies into the clinic, Dr. Witzigmann co-founded and leads the LNP-nucleic acid company NanoVation Therapeutics 

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Dr. Jayesh Kulkarni

Dr. Kulkarni obtained his PhD from the University of British Columbia and has over 12 years of academic and industry experience in the nanoparticle drug delivery field. He has published over 40 peer-reviewed articles in prestigious journals and 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.

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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.

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