What if oncologists could degrade and eliminate disease-driving proteins rather than simply block them — and do it with a modular platform that works across cancer types, crosses the blood-brain barrier, and delivers chemotherapy at the same time?

This new class of protein-degrading drugs are called nanoparticle-mediated targeting chimeras, or NPTACs, for short.

This new approach, outlined in a recent Nature Nanotechnology perspective, builds on research from Columbia University and the University of Technology Sydney published in October 2024, which demonstrated that nanoparticles decorated with targeting antibodies can drag cell-surface proteins into the lysosome — the cell’s waste-disposal system — for destruction.

In mouse models, NPTACs significantly slowed the growth of breast tumors and extended survival in glioma.

“The most immediately valuable capability is that this nanoparticle technology can add a targeted protein degradation function to what nanomedicine already does well — namely, controlled tissue-selective delivery”, said Kam Leong, PhD, Samuel Y. Sheng Professor of Biomedical Engineering at Columbia University, New York City, a co-senior author of both papers.

In practical terms, clinicians could potentially use a single NPTAC platform to both eliminate a disease-driving protein and co-deliver a chemotherapeutic or immunotherapy payload — optimizing exposure while reducing off-target toxicity.

How Destruction Could Beat Inhibition

For most of pharmaceutical history, drugs have worked by blocking proteins — parking in an active site to prevent function. It’s effective but imperfect. Block one function of a multitasking protein and the others keep running. Remove the drug and the protein resumes immediately.

Raymond Deshaies, PhD, Professor Emeritus of Biology at the California Institute of Technology (Caltech) and pioneer in targeted protein degradation, explains why destroying proteins matters clinically: “The protein might have multiple functions, and if you make a conventional inhibitor, you’re inhibiting one function at a time. With a degrader, since you’re getting rid of the entire protein, that’s advantageous.”

Small-molecule degraders like PROTACs — proteolysis-targeting chimeras — work catalytically: a single molecule can destroy its target, get released, and destroy another. And because the target is gone rather than merely occupied, the cell must rebuild it from scratch before the disease pathway resumes.

PROTACs have been in development for over two decades and validated the therapeutic potential of targeted protein degradation. Vepdegestrant, developed by Arvinas and Pfizer to destroy estrogen receptor alpha, recently extended progression-free survival in patients with ESR1-mutant breast cancer in a Phase 3 trial, leading the FDA to accept its New Drug Application and grant it Fast Track designation.

But PROTACs face intrinsic limitations: they work inside cells and depend on the proteasome, which means they struggle to reach membrane receptors on the cell surface, secreted proteins in circulation, and protein aggregates too large for the proteasome to process.

NPTACs exploit a different pathway. Instead of needing to slip inside the cell to hunt down targets, NPTACs latch onto proteins on the cell’s exterior and force the cell to swallow the entire complex — routing it directly to the lysosome for digestion.

A Modular Platform

The concept emerged from frustration with conventional degrader chemistry. Bingyang Shi, PhD, co-senior author of both papers and chair professor of nanomedicine at the University of Technology Sydney in Sydney, Australia, explained that his group spent years hitting the same bottleneck: even minor structural modifications to optimized compounds proved difficult to synthetically produce.

“Once we framed degraders as modular units rather than as a single inseparable molecule, a broader design space became obvious,” Shi said. If the components don’t need to be embedded within one small molecule, then nanoparticles could organize the same functional modules on a programmable scaffold.

The group’s 2024 study demonstrated the concept works across diverse nanoparticle formulations — polymeric particles, liposomes, exosomes, and gold nanoparticles — all successfully degrading clinically relevant targets including HER2, epidermal growth factor receptor (EGFR), PD-L1, and mutant p53, the tumor suppressor mutation driving roughly half of all human cancers that has long resisted targeted therapy.

Unlike small-molecule degraders, however, NPTACs are not truly catalytic as the nanoparticle gets engulfed and digested along with its cargo. Shi acknowledged that some groups are designing nanoparticles with recycling capability but called the concept “largely hypothetical at present.”

EGFR, a protein on the cell surface that receives signals telling the cell to grow and divide, has been the group’s strongest success. It’s well-characterized, broadly expressed, and shows robust internalization and consistent degradation.

While still strictly theoretical in human patients, successfully destroying this receptor could bypass the resistance mechanisms that eventually defeat standard therapies in heavily EGFR-driven malignancies like non-small cell lung cancer, colorectal cancer, and the gliomas, mentioned earlier.

Mutant p53, however, remains considerably more challenging. “Distinguishing mutant p53 from its wild-type counterpart remains a significant obstacle,” Shi noted. The protein is also primarily intracellular, requiring not just selective recognition but efficient trafficking to the appropriate subcellular compartment.

By bypassing the complex “molecular matchmaking” that PROTACs require to function inside the cell, NPTACs significantly simplify the drug development process.

“PROTACs work mainly for intracellular proteins,” said Leong. “What this technology has shown is that it could expand the protein of interest from intracellular to extracellular proteins.”

Because the platform is modular, the same nanoparticle scaffold can carry different targeting molecules like antibodies, peptides, or aptamers against different disease targets. Instead of years of painstaking chemistry to design a new PROTAC for each protein, researchers could swap ligands on a proven backbone.

Leong emphasized what he calls “push-pull” functionality. “This is a dual-function approach — removing the damaged or dysfunctional protein and then delivering the therapeutic payload,” he said. “Push and pull, which is something that the conventional PROTAC cannot do.”

When asked whether this approach opens doors beyond oncology — into autoimmune, metabolic, or neurologic disease — Leong’s answer was direct: “Definitely. That is the potential of what we propose.”

Targeting Is Not Access

Deshaies sees specific clinical niches where NPTACs could succeed but urges caution about broader claims. “Nanoparticles have been promising all kinds of things for decades that haven't been delivered,” he observed. “I remain skeptical.”

His concern centers on a distinction that has bedeviled nanomedicine for years: the difference between targeting and access. “You could have a ligand that allows you to bind to a very specific cell type,” Deshaies explained. “But you have to get to that cell type to bind it.” Getting nanoparticles deep into solid tumors or across the blood-brain barrier remains a fundamental challenge, one that no amount of surface decoration fully solves.

Shi agreed with the distinction. “Tissue targeting and tissue access are different problems,” he said. “One can engineer highly specific targeting ligands, but if the particle cannot physically penetrate the tissue — because of vascular barriers, stromal density, or rapid systemic clearance — targeting becomes irrelevant.”

But he framed the challenge as a design direction rather than a fatal limitation. The modular nature of NPTACs allows integration of advances in nanoparticle engineering — size optimization, surface modification, barrier-navigation strategies — as they mature.

Where might NPTACs work first? Deshaies pointed to situations where tissue penetration isn’t the bottleneck: “If you’re targeting something that’s floating in blood and lymph — hematological cancers, for example — these are cancers where the nanoparticle doesn’t have to somehow navigate” through dense tissue.

Shi concurred. For a first-in-human trial designed to sidestep the access problem entirely? “We’d start with a circulating blood cancer,” he said, “because the delivery barrier is lowest and we can directly measure target degradation in patient cells as a definitive mechanistic readout.”

The Road to Patients

When might clinicians see these approaches? “Human clinical trials in 4-5 years,” Leong estimated. “But if it’s a product on the market, it will be at least 10 years.”

Shi’s lab is now pursuing two parallel tracks: translational work addressing clinical trial readiness and mechanistic research to make the platform more predictable.

“The most challenging technical problem we face is integrating pharmacokinetics, biodistribution, and intracellular trafficking into a quantitatively predictive framework,” he said. “Ultimately, we are addressing a systems-level nano-bio interface problem, not merely a synthetic chemistry challenge.”

NPTACs build on decades of nanomedicine development using FDA-approved materials with established manufacturing. The infrastructure exists. What remains is proof-of-concept in the right indication.

The single biggest obstacle, Leong reflected, “is not a missing piece of chemistry. It’s choosing the clinical application where we can demonstrate clinical relevance without asking clinicians and regulators to take a leap of faith.”

Whether that turns out to be hematologic malignancies, circulating targets, or carefully selected solid tumors will determine how quickly this technology moves from mouse models to patients.