How Extracellular Vesicles and Nanoparticles are Transforming Drug Delivery

When I reflect on how medicine has evolved over my lifetime, the shift is remarkable: from a scatter-gun approach to treatment to the targeted precision of today. We are inching ever closer to that long-imagined “magic bullet.”

How often do you see people taking tablets like they are a share pack of sweets — some small ones, some very big ones, assorted colours, some for Monday, others every day, some every other day, with food, without food, only in the morning, maybe before you go to bed. Maybe you need to stand on one leg and poke your tongue out.

Then there are contraindications, and the ‘tweaking’ of the dose because the regime makes you dizzy and you fall over a lot. Clearly drug A is interacting with drug B, and you have condition X which enhances the efficacy of the dose. I get the feeling this world of controlled pharmaceutics is more chaotic than it appears.

I am not the only one it seems — there is a global push to resolve rather than treat. Academic groups such as the Controlled Release Society (CRS) [1] are home to experts dedicated to the delivery of drugs, cosmetics, flavours, fragrances, pesticides and other actives. CRS members are creating the future of delivery science and technology through fundamental delivery research, development, regulatory science, and clinical translation. [1]

What you’ll learn

This article explores how two breakthrough platforms — nanoparticles and extracellular vesicles (EVs) — are reshaping modern drug delivery.

You’ll discover:

• How EVs and nanoparticles evolved, and why they’re now central to precision medicine.
  
• Real examples of how researchers are using nanocarriers, from lipid nanoparticles and PLGA systems to metal–phenolic networks and bacteriophage-encapsulating liposomes.
  
• Why EVs, nature’s own delivery vehicles, may hold the key to safer and more targeted therapies.
  
• How hybrid EV–LNP systems could bridge the best of both worlds.
  
• What challenges remain before these technologies reach full clinical potential.
  

A brief history: EVs and nanoparticles

Extracellular vesicles (EVs) have had a bit of a slow start if you include the 1666 finding of Marcello Malpighi – the physician that described fibre filaments that remained in a blood clot post washing [2].

Fast forward a few centuries and we arrive at “platelet dust” — the term Peter Wolf coined to describe the subcellular coagulant material he observed [3]. There is a terrific article outlining the history of EVs (A brief history of nearly EV‐erything – The rise and rise of extracellular vesicles) [4].

The advent of nanoparticles (NPs) for the delivery of drugs is very contemporary compared to EVs, however both modalities seem to be gaining popularity.

Owing to the inherent shortcomings of traditional therapeutic drugs in terms of inadequate therapeutic efficacy and toxicity in clinical treatment, nanomedicine designs have received widespread attention with significantly improved efficacy and reduced non-target side effects. [5]

Figure 1. The trend of publications related to nanomedicines over the past decades. Data are derived from the Web of Science utilizing the keyword “nanomedicine∗”. [5]

As exemplified by figure 1, the global research response in nanomedicine is staggering, with no indication that this trend will abate. Extracellular vesicles seem to be enjoying similar rockstar status.

Figure 2. Exponential curve fitting for the growth in publications in the EV field between 1987–2023. [6]

Why are these modalities so popular in research? Will they be pivotal in future medicine?

This article will explore how these two platforms have the potential to transform medicine, hailing in a new era of disease treatment.

The Promise of Nanoparticles in Drug Delivery

Grasping the true scale of a nanometre can be surprisingly difficult to wrap our heads around. Try this: imagine half an inch (12.7 mm) stands for one nanometre. If that tiny length is a nanometre, then one metre would scale up to about 12,700 km — roughly the diameter of Earth.

In other words, compared with a metre, a nanometre is vanishingly small.

Nanoparticle delivery for medicinal purposes has had some astounding impacts in its relatively short history. The biggest vaccination rollout ever — the COVID‐19 vaccine — saved millions of lives, equating to a global reduction of 63% in total deaths during the first year of vaccination [7].

A common misconception is that all nanoparticles are lipid nanoparticles (LNPs). Not so. While much research is centred around LNP encapsulation of RNA, there are many other formulation options.

PLGA (poly(lactic-co-glycolic acid)) is a biodegradable and biocompatible synthetic polymer widely used in medical devices and drug delivery systems. It can be fabricated into nanoparticles, nanocarriers, nanoscaffolds, and various other nanostructures as required [8].

There are challenges for many nanoparticles used for drug delivery — especially if you are trying to target anywhere other than the liver. We encapsulate treatments for stealth and protection: to avoid the body recognising them as foreign, and in the case of RNA, to protect it from RNases.

Adding a targeting moiety isn’t simple. If we do, is it like moving your nanoparticle out of camo and into hi-vis?

A new development full of promise is Metal Phenolic Networks (MPNs). At the 14th Nanomedicines Conference on Sydney Harbour, Prof. Frank Caruso (University of Melbourne) described the effectiveness of MPNs in targeting specific organs — a breakthrough that could enable organ-specific nanoparticles for drug delivery [9,10].

Another exciting innovation comes from Yue (Eric) Cao et al. at the University of Sydney, who formulated liposomes to encapsulate bacteriophages. In the context of antimicrobial resistance, this could be a significant discovery. “Liposome-encapsulated bacteriophages offer promising potential for targeted antimicrobial therapy against multidrug-resistant infections, by enhancing phage stability and delivery” [11].

The study revealed that the Micropore Technologies AXF Mini encapsulated bacteriophages at a far greater percentage (>90%) and was well-suited for large-scale manufacturing [11].

At the University of South Australia, Prof. Clive Prestidge has had success repackaging previously approved drugs — taking them from tablet form to nanoparticle-encapsulated formulations. Lipid-based nanocarriers have been shown to enhance gentamicin effectiveness against E. coli biofilms [12], reducing dosage and enabling more direct routes of administration.

All current FDA-approved LNP formulations contain four lipids (Fig. 3): (1) an ionizable cationic lipid, (2) 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), (3) cholesterol, and (4) a polyethylene glycol (PEG)-lipid conjugate. These components improve nanoparticle stability, encapsulation, and cellular uptake [13].

Figure 3. Simplistic illustration of LNP and its components, showing possible nucleic acid cargo [13].

Ionizable cationic lipids (typically containing tertiary amines) serve two key functions: facilitating nucleic acid encapsulation and mediating endosomal membrane disruption to enable release to the cytosol. They may also aid cellular uptake via interactions with negatively charged cell membranes or plasma proteins [13].

Extracellular Vesicles (EVs): Nature’s Delivery System

Associate Professor Joy Wolfram (AIBN, Queensland) provides a compelling analogy for extracellular vesicles (EVs): they are the text messages cells use to communicate. By studying these messages, we can eavesdrop on the information cells exchange — whether beneficial or harmful.

Healthy cells might send EVs to promote tissue repair; cancer cells can use them to support tumour growth and spread. Understanding these signals not only offers early markers of disease but may enable us to intercept or block harmful messages.

What makes an EV? How does the origin change the nomenclature? What are the various types?

The International Society for Extracellular Vesicles (ISEV) updates its “Minimal Information for Studies of Extracellular Vesicles” (MISEV) guidelines regularly. Their website (https://www.isev.org) offers excellent educational resources, including a MOOC and the latest research.

Interestingly, the Chinese Journal of Laboratory Medicine [14] describes ultrasonic nanofiltration as a rapid, automatable EV separation method that improves purity and processing speed — an approach not yet reflected in ISEV protocols.

EVs are present in nearly every bodily fluid. Those from the plasma membrane are ectosomes (microvesicles), while exosomes arise from multivesicular bodies. There are also exophers, migrasomes, oncosomes, blebbisomes, and EVs even in bacteria and archaea.

TEM images from Dr Stephen Kidd (University of Adelaide) show stunning examples of Staphylococcus EV budding.

As natural products of cells, EVs can achieve biodistribution without immune attack — a key advantage over synthetic carriers.

EVs can traverse the blood–brain barrier (BBB) through several mechanisms, including clathrin- or caveolae-mediated endocytosis, adsorptive transcytosis, and micropinocytosis. Once internalised, RAB proteins guide them for either degradation or release [15].

Loading Therapeutics into EVs

There are two main methods:

1. Cell-based (endogenous) — manipulating donor cells through incubation or transfection, allowing the desired cargo to load naturally before harvesting the released EVs [16].

2. Non-cell-based (exogenous) — loading isolated EVs via sonication, electroporation, or transfection reagents. This approach enables incorporation of siRNA, miRNA, proteins, CRISPR/Cas9, and other therapeutic molecules [16].

Surface modification can further enhance targeting. For instance, tailoring EVs as more precise vaccine carriers could improve both efficacy and safety.

While EVs are often described as more potent or better tolerated than LNPs, evidence is still emerging. Cytokine responses tend to be lower with EVs, but dosage, source, and route of administration all play roles.

The surface proteins of EVs heavily influence their biodistribution — critical for achieving reliable therapeutic delivery [17].

Nanoparticles vs EVs

Type of Particle	Production Method	Toxicity	Cell Transfection Capacity	Encapsulation Efficiency	Isolation/Purification	Scalability	Targeting	Biomarker Capacity
Nanoparticles (e.g. LNP)	Chemical synthesis	Chemistry-dependent	Highly variable	>80%	N/A	Readily scalable	With moiety	Can be engineered
Extracellular Vesicles	Natural cellular	Self – non-toxic	Highly variable	Can be poor	Improving rapidly	Limited presently	Natural or with moiety	Yes, natural
Hybridisation (LNP–EV)	Blend	Variable	Enhanced as hybrid	High	Inherits EV challenges	Promising	Engineered + natural	Mixed

Hybridisation of LNPs and EVs could offer the best of both worlds. Hu et al. reported 99% loading efficiency in DOTAP/cholesterol liposomes, slightly decreasing to 97% post-extrusion in hybrids — with the hybrids specifically targeting bone and promoting osteogenesis [18,19].

However, evidence of clinical effectiveness remains limited.

The Road Ahead

EVs face added development challenges and regulatory hurdles — including variability, low nucleic acid loading, and undefined mechanisms. Bader et al. [19] listed over 100 clinical trials using LNPs, but only three involving EV-based systems.

Still, the potential is vast. History reminds us that RNA was once dismissed as “junk.” EVs could prove equally transformative in decoding disease and refining therapy.

Meanwhile, lipid nanoparticle technologies continue to evolve: RNA manufacturing is more efficient, next-generation nanocarriers are emerging, and targeting is becoming more precise.

Adding EVs to this innovation landscape sets the stage for a new era of accelerated biomedical discovery — guided by AI and advanced material design.

ATA Scientific’s Commitment

ATA Scientific is proud to support this momentum. With more than 35 years serving Australian research — and many decades ahead — we remain committed to empowering scientists as they shape the future of drug delivery and precision medicine.

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