Marco Lolaico is a DNA nanotechnology researcher turned science communicator, and the founder of Plenty of Room (https://plentyofroom.beehiiv.com/), a newsletter covering AI-driven protein design, DNA nanotechnology, and deep tech life science startups.
With a PhD from Karolinska Institutet and experience as a biomaterials startup co-founder, Marco writes for researchers, founders, and investors who want to stay ahead of what's coming at the frontier of biology.
Originally published in Plenty of Room (https://plentyofroom.beehiiv.com/p/polymer-peptides-hybrids-grove-biopharma-targets-undruggable-diseases). Republished here with his permission.
Intracellular protein-protein interactions are crucial to treating diseases, but many drugs can’t reach them. This makes them the most ambitious target in biotech!
And Grove Biopharma is building the tools to reach them, using polymer-peptide hybrids to enter cells and cure diseases. How does it work? What does science say? What's in their pipeline?
Well, in this issue of the Deep Tech Breakdown, we go deep into Grove’s technology! It’s a return to my biotech origin.
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Grove Biopharma: The Breakdown
Grove Biopharma targets intracellular protein-protein interactions using their protein-like polymers.
Company Basics
Grove Biopharma was founded in 2020 in Chicago, USA. They're building a new class of drugs to target what everyone else can't reach: proteins inside cells.
The Problem: Targeting Intracellular Proteins
Most interesting disease-causing proteins hide inside cells.
The problem is: how do you target them? Small molecules can diffuse through membranes easily, but they need well-defined pockets to bind to. And many intracellular proteins have smooth surfaces with nothing to grip.
This is especially true for protein-protein interaction surfaces.
Protein-protein interactions (PPIs) control everything, from cell metabolism to cancer pathways (MYC, KRAS) to neurodegeneration (Tau). Everyone would love to target them, but small molecules don’t work.
Biologics (antibodies and peptides) look perfect, since they can bind almost anything. But they have their own struggles:
Size: Antibodies are too big to cross cell membranes.
Cell metabolism: Inside a cell, they can be trapped or degraded before reaching the target.
Stability: Peptides especially suffer from stability issues; some promising ones only last a few minutes in physiological buffers.
The result is that there is a huge class of disease-driving targets we can’t touch today. Unlocking them would transform cancer and neurodegeneration treatment!
Grove’s Solution: Bionics BiologicsTM
Grove’s solution? Bionics BiologicsTM.
Great name. Grove combined synthetic chemistry with biology in a new way to create protein-like polymers (PLPs). PLPs were invented by Nathan Gianneschi, professor of Chemistry at Northwestern University (USA) and scientific founder of Grove Biopharma.
Protein-like polymers combine synthetic chemistry and biology, creating polymers that resemble proteins, can enter cells, and have higher stability.
PLPs are built from a polymer backbone with peptide branches, using a technique called living polymerization. These peptide-polymer hybrids mimic the proteins' globular 3D shape. This approach gives you advantages over “simple” peptides:
Stability: They’re more resistant to proteolysis in physiological buffers.
Cell penetration: Customized charge makes them amphipathic so that some designs can cross membranes.
Binding power: They maintain the peptide’s binding, sometimes improved by multivalent effects.
And Grove doesn’t need to invent new peptides. They aim to take existing ones that work in tubes but fail to enter the cell, and make them cell-penetrant. They can use validated targets and chemistries, partnering with other companies, or develop their own peptides.
Pretty smart!
The Science Behind the Company
PLPs weren’t invested yesterday.
Nathan Gianneschi’s lab developed them all the way back in 2013, and the PLP technology has been published in many peer-reviewed articles over the last decade, while translation is more recent.
Foundational chemistry work (2013-2020)
PLPs first appear in a publication in Polymer Chemistry in 2013. The team noticed their interesting properties, especially the resistance to proteases (JACS article in 2014), and started studying them more in depth.
This article in Accounts of Chemical Research from 2020 is the most complete overview of PLPs I’ve found! The academic group investigated the resistance to proteases in this ACS Central Science article in 2021, and the foundational work is still going on (Chemical Science).
From the chemistry lab to the cell: translational work (2023 - present)
Three of the most interesting papers exploring PLPs’ translational potential:
Science Advances 2023: First PLP drug, targeting the membrane protein CD36 to treat macular degeneration in mice and outperforming the current standard of care. CD36 is extracellular, so the PLPs didn’t need to enter the cell.
Science Advances 2024: PLPs penetrate neurons, target the mitochondria, and avoid renal clearance in mice, staying in circulation 2000x longer than peptides. PLPs prevented pathology in mouse models of Huntington disease.
Nature Communications 2026: The team from Grove and Northwestern University created a new class of PLPs named HYDRAC. It combined targeting and degradation (like PROTACs). Polymeric structures with a targeting peptide and a degradation-tagging peptide. HYDRAC successfully degraded MYC and KRAS in mice and reduced tumor growth.
A strong publication record! The polymeric system is well characterized, and the translational results are solid. They also have licenses on the patents for the system, which I think are owned by Northwestern University.
The Pipeline: What are They Going After?
This scientific excellence translates into a strong pipeline of targets.
They have 6 targets across cancer and neurodegeneration:
AR/AR-V7: A driver of resistance to treatments in prostate cancer. Their approach here is target-and-degrade, maybe with the HYDRAC approach. They target the oncogenic driver (AR) and the resistance mechanism (AR-V7).
SHOC2/MRAS/PP1C: 3 proteins involved in the RAS-RAF pathway, often dysregulated in cancer. They want to disrupt SHOC2, a previously “undruggable” target. This could make it possible to treat a variety of cancers, from non-small cell lung to colorectal and pancreatic.
MYC: Myc is one of the most well-studied cancer proteins, involved in over 70% of cancers! Here, they target the interaction between Myc and TAD.
WDR5/MYC: The target here is WDR5, a protein that creates a complex with Myc. When you degrade WDR5, the pathway is disrupted. Myc and WDR5 are involved in many cancers, including pancreatic, breast, prostate, and more.
Tau: Tau protein leads to neurodegeneration in Alzheimer's disease. In a recent preprint, researchers from Grove showed that PLPs can stop Tau aggregation. The hope is to stop or even reverse the neurodegenerative process.
Keap1-Nrf2: This pathway is involved in defence from oxidative stress. They aim to disrupt the Keap-Nrf2 interaction, which might turn on the defence system and improve the outcome of neurodegenerative diseases. This approach showed protection against myocardial infarction in Advanced Materials in 2024.
An ambitious pipeline for sure!
Technical Risks: Where Could This Fail?
Impressive work! But biotech is hard; there’s always something that might not work. These are the risks I can see:
Fundamental science gaps
Most drugs fail in phase I or phase II clinical trials. A failure in phase I means that the toxicity in patients was too high, and in phase II that the drug didn’t work as well as expected. Some of the targets that Grove is going after are biologically well characterized, but they never worked out. Another unknown is the toxicity of PLPs in humans, especially with redosing.Scalability challenges
I’m no polymer scientist, but scaling in biotech is a common problem. Now, polymer science is decades ahead of biotechnology in this. But does living polymerization scale well? Combining with peptides adds even more complexity. From what I’ve found, it can be delicate to scale and require downstream purification, especially if they use metal catalysts. On the bright side, peptides’ production is easily scalable!
Translational barriers
The road to a drug is long! Even with the good pre-clinical work Grove has done until now, there are still barriers ahead. I’m no expert on biotech, so take this section as you wish. The next big step would be to get an investigational new drug (IND) designation, so that they can start testing in humans. For this, they need more pharmacology and safety assessments.
Competitive Landscape: What They’re Up Against
Grove is mostly focused on intracellular targets, where small molecules dominate, and most other biologics struggle. But there are new, competing technologies out there! Two to highlight:
Macrocyclic peptides
Macrocyclic peptides bridge the gap between small molecules and biologics. These ring-shaped chains of amino acids combine the high target binding of peptides with better stability. Similar to what Grove is doing! But without multivalent binding. There are over a dozen FDA-approved macrocyclic peptide drugs for conditions from high cholesterol to myeloma.
PROTAC
The inspiration for the HYDRAC system we saw earlier. PROTACs (proteolysis targeting chimeras) are a new technology aimed at binding a target protein and tagging it for degradation. This approach works better for targets where small molecules struggle. PROTACs are made of 2 covalently linked small molecules: one binds the target protein, the other recruits an ubiquitin ligase, which targets the target for degradation. The first PROTAC was approved by the FDA just in May 2026, for use against specific breast cancer.
Why Grove Could Win
Grove looks like it could pull this off, at least on paper.
They have a few things going for them:
Strong team
Grove’s leadership brings a lot of experience. CEO Geoffrey Duyk, PhD, has >30 years in pharma and biotech; Paul Bertin, PhD (CTO), has 40 patents in synthetic chemistry; Robert Campbell, PhD (CSO), is an expert in molecular cancer therapeutics with over 130 publications!
They invented the platform
In addition to the great leadership, Nathan Gianneschi (scientific founder) literally invented PLPs. This brings the IP and the know-how from more than a decade refining the platform. That gives them a head start on competitors.
Great timing
Peptides are hot, polymer chemistry is maturing, and PLPs slot perfectly into both trends. Five years ago, this would have been much harder. Five years from now, there might be another 10 companies doing similar things. Grove is in the right spot!
Platform, not single drugs
Grove’s biggest bet isn’t an individual candidate, but the platform itself. If PLPs solve intracellular delivery and stability challenges, the same chemistry could address dozens of targets. In addition, Grove isn't competing where existing drugs already work. Instead, the company is focusing on proteins that have historically been difficult or impossible to drug.
The Bottom Line
The science works.
PLPs deliver peptides into cells and keep them stable; the mouse data proves that. The real question is: does it translate to humans? That's always the gap in biotech!
What comes next? Grove needs IND designation within 2-3 years → more pharmacology and safety work. Then clinical trials in humans. And that’s where most drugs end up dying.
But if it works, Grove might have more than a good drug. They would have proved that synthetic polymer-based therapeutics can work, and turn it into a platform. That opens new territory for intractable targets!
For now, the team is strong, the science is solid, and they're targeting problems everyone else considers impossible. That's a strong recipe!
If you made it this far, thank you! What do you think of PLPs? Do you think that they could be a valuable addition to our drug tool? Do you like this format? Reply and let me know!
Thanks again to Marco Lolaico for letting us republish this article. Go check out his publication Plenty of Room!
