Cracking the Cell: How Bacterial Nanosyringes Are Revolutionizing Drug Delivery
Harnessing nature's nanomachines to reach the 85% of intracellular targets that have remained undruggable
The Intracellular Drug Delivery Challenge
For decades, drug developers have faced a frustrating reality: while we've identified thousands of biologically important targets inside our cells, the vast majority remain "undruggable." Current estimates suggest that as many as 85% of intracellular proteins cannot be reached by existing therapeutic modalities 1 .
The problem lies in delivery. Small molecules struggle to bind to the flat surfaces of protein-protein interactions. Antibodies, enzymes, and peptides—despite their high specificity—cannot cross the cell membrane. Lipid nanoparticles (LNPs) typically shuttle their cargo to the liver regardless of where it's needed, and viral vectors come with dosing, immunogenicity, and manufacturing challenges 1 . This delivery bottleneck has left many of the most promising therapeutic targets tantalizingly out of reach.
"There's a huge universe of biology that we know is relevant, but simply haven't been able to reach," said Joe Healey, the company's founder and CEO. "We know those targets matter, and now we know how to get to them" 1 .
Nature's Nanomachines: A Billion Years of Delivery Evolution
The story of nanosyringes begins not in a laboratory, but in nature, where bacteria have been perfecting the art of intracellular delivery for millions of years. These syringe-like structures, known scientifically as extracellular contractile injection systems (eCIS), evolved as biological weapons that allow bacteria to inject proteins directly into host cells 1 2 .
The discovery of these nanomachines has some unlucky insect larvae to thank. Microbiologist Nick Waterfield, now at the University of Warwick and co-founder of NanoSyrinx, was studying Photorhabdus bacteria when he noticed something extraordinary. One particular gene cluster was so potent that it killed wax moth larvae within 15 minutes—far faster than other virulence factors 2 .
"When we got our first look at them down the electron microscope, it was a bit of a 'Wow!' These really do look like syringes because we saw them in both extended and contracted forms," Waterfield recalled. Subsequent work with immunogold antibodies confirmed that toxins were being "squirted out the end" of these structures 2 .
Since these initial observations, scientists have identified nanosyringe sequences in many different bacterial species through bioinformatic analyses. The systems are produced in a manner similar to phage viruses—a subpopulation of bacterial cells activates the genes, fills with the syringe-like structures, then lyses to release them into the environment 2 .
Engineering Nature's Syringes for Medicine
NanoSyrinx has transformed these bacterial weapons into a programmable platform for therapeutic delivery. The company's technology centers on a genetically encoded platform that can be produced using simple microbial fermentation 3 .
1. Production
"The magic happens, and the payloads are loaded into the nanosyringes. The nanosyringe is built... They sit there quite happily as loaded nanosyringes full of payload until you crack the E. coli open and then do the protein purification," Healey explained 2 .
2. Targeting
Cell-binding arms at one end selectively recognize specific cell-surface targets.
3. Injection
Once anchored, the structure contracts, subtly piercing the membrane and injecting its protein payload directly into the cytosol.
4. Bypass Endocytosis
This mechanism bypasses endocytosis—the common fate of antibody and nanoparticle conjugates—thus avoiding lysosomal degradation and ensuring the payload arrives intact and functional 1 .
| Delivery Method | Advantages | Limitations |
|---|---|---|
| Bacterial Nanosyringes | Direct cytosolic delivery; modular targeting; diverse payload capacity; genetically encoded | Relatively new technology; long-term immune response still being characterized |
| Lipid Nanoparticles (LNPs) | Proven clinical success with mRNA vaccines; well-established manufacturing | Primarily accumulate in liver; limited targeting capabilities; endosomal trapping |
| Adeno-Associated Viruses (AAVs) | Long-lasting expression; proven gene therapy platform | Dosing limitations; immunogenicity concerns; manufacturing complexity |
| Antibody-Drug Conjugates (ADCs) | Target specificity; proven clinical platform | Limited to small molecule payloads; dependent on internalization |
One of the platform's most significant features is its speed. Starting with only the gene sequence of a protein, NanoSyrinx can design, produce, and validate a Nanosyringe candidate in vitro in as little as 8-10 weeks 1 . This rapid turnaround accelerates early validation and lowers risk, enabling the exploration of multiple therapeutic hypotheses in parallel.
The SPEAR Experiment: A Closer Look at a Pivotal Study
A recent landmark study published in Nature Communications demonstrates just how versatile these engineered nanosyringes have become 4 . The research team developed a system termed SPEAR (Spike Engineering and Retargeting) that significantly expands the capabilities of bacterial nanosyringes.
- Spike-mediated cargo loading: Inspired by related bacterial injection systems, the team fused cargo domains directly to the spike complex at the base of the nanosyringe, enabling delivery of folded proteins and ribonucleoproteins that would be unfolded and inactivated by traditional loading methods.
- In vitro cargo loading: By engineering the spike tip protein (Pvc10) to self-assemble onto pre-formed nanosyringes in vitro, the team created a method to load synthetic cargos that might be difficult to produce biologically.
- Antibody-based retargeting: The researchers inserted bioconjugation tags into the nanosyringe's targeting element, enabling covalent attachment of full-sized antibodies and single-chain variable fragments (scFvs) for precise cell targeting.
| Experimental Approach | Key Result | Significance |
|---|---|---|
| Spike-mediated RNP delivery | Successful delivery of functional Cas9 ribonucleoproteins | First demonstration of folded RNP delivery using bacterial nanosyringes |
| In vitro ssDNA loading | Efficient delivery of single-stranded DNA oligonucleotides | Expands payload scope to include nucleic acids for gene editing applications |
| Antibody-based retargeting | Specific targeting of cells using scFvs and monoclonal antibodies | Greatly expands the cell types and tissues targetable by the system |
| In vivo cell depletion | ~7% bulk depletion of target cells in mouse spleen | Demonstrates functionality in live animals with minimal off-target effects |
Perhaps most impressively, the researchers showed that multiple engineering approaches could be combined. Nanosyringes lacking both cargo and targeting moieties could be functionalized in a single complementation reaction, simultaneously equipped with both Cas9 ribonucleoproteins and cell-targeting antibodies 4 .
The specificity of these retargeted nanosyringes was particularly striking. When applied to mixed cocultures of different cell types, antibody-conjugated nanosyringes selectively depleted only their target populations, demonstrating the precision of this delivery system 4 .
The Scientist's Toolkit: Key Research Reagents
The engineering of bacterial nanosyringes requires a sophisticated toolkit of molecular biology reagents and genetic components. The SPEAR study highlights several key elements that enable this technology:
| Research Reagent | Function in Nanosyringe Engineering | Example from SPEAR Study |
|---|---|---|
| Spike complex proteins (Pvc8/Pvc10) | Forms the membrane-penetrating tip of the nanosyringe; platform for cargo fusion | Fused to Cas9 for RNP delivery; fused to HUH endonuclease for ssDNA loading |
| Targeting element (Pvc13) | Determines cell specificity through surface receptor binding | Modified with SpyTag or SNAP-tag for antibody conjugation |
| Bioconjugation tags (SpyTag/SNAP-tag) | Enables covalent attachment of targeting antibodies to nanosyringes | SpyTag conjugated to SpyCatcher-fused scFvs; SNAP-tag conjugated to BG-labeled mAbs |
| HUH endonucleases | Specialized enzymes that bind single-stranded DNA | Fused to Pvc10 for loading and delivery of ssDNA oligonucleotides |
| Antibodies and binding domains | Provide cell-type specificity through surface antigen recognition | Anti-HA scFv, anti-CD3 mAb, anti-MHCII nanobody, anti-EGFR DARPin |
This modular toolkit enables researchers to mix and match components based on their specific delivery needs, creating a versatile platform that can be adapted for various therapeutic applications.
The Future of Intracellular Medicine
The implications of targeted intracellular protein delivery are wide-ranging. As areas where intracellular delivery challenges are especially acute, cancer and ophthalmology are natural starting points for NanoSyrinx's internal programs 1 .
| Therapeutic Area | Potential Application | Key Advantage |
|---|---|---|
| Oncology | Targeted delivery of cytotoxins, protein degraders, or immune modulators | Cell-type specificity reduces off-target toxicity; direct cytosolic delivery avoids lysosomal degradation |
| Ophthalmology | Non-viral delivery of therapeutic proteins to retinal cells | Potential improvement over viral vectors in terms of immunogenicity and dosing limitations |
| Gene Therapy | Delivery of gene editing components (Cas9 RNPs, base editors) | Avoids limitations of viral vectors; enables transient rather than permanent expression |
| Cell Engineering | Reprogramming immune cells (e.g., CAR-T) for therapeutic applications | Targeted delivery to circulating immune cells demonstrated in vivo |
"This is about expanding the boundaries of what therapeutics can do," noted James Lapworth, CBO at NanoSyrinx. "With Nanosyringes, we can deliver the protein itself directly to the target inside the cell. That opens an entirely new space of undruggable targets to intervention" 1 .
"Most existing delivery systems are either non-specific like LNPs, or limited in what they can carry like ADCs," Lapworth explained. "Our Nanosyringe platform takes advantage of what nature has already perfected to deliver proteins. All we've changed is which proteins are delivered, and to which cells" 1 .
In oncology, Nanosyringes could selectively deliver cytotoxins or protein degraders to tumor cells, or intracellular enzymes to rewire resistant tumors. The platform's ability to target specific cell types could dramatically reduce the off-target toxicity that plagues many current cancer therapies. Proof-of-concept work with AstraZeneca successfully demonstrated functional delivery of an enzyme degrader against a classic intracellular oncology target—something the pharma's previous delivery attempts had struggled to achieve 1 .
In cell and gene therapies, Nanosyringes could serve as targeted tools for precise cellular engineering without the limitations of viral vectors.
The technology also represents a significant shift in how we think about drug development.
As the platform continues to develop, the goal is to establish Nanosyringes as a new therapeutic modality in medicine, much like antibodies and viral vectors before them. With a growing body of evidence, seasoned backers, and a strategy designed to amplify its impact, NanoSyrinx and similar companies working in this space are poised to expand the therapeutic frontier by redefining what's possible in intracellular medicine.
The journey from discovering these fascinating bacterial structures to harnessing them for medicine exemplifies how observing nature's solutions can lead to groundbreaking technologies.
As research in this field progresses, these tiny bacterial syringes may well become essential tools in our therapeutic arsenal, finally unlocking the vast potential of intracellular targets that has remained out of reach for so long.