Antibody-based drugs are among the backbone of many drugs available today. Until now, the inside of the cell has been off limits; that barrier is beginning to crack. This is the first of several stories describing how the power of antibodies can be harnessed to treat diseases both inside and outside the cell.

These proteins recognize specific structures on the surface of cells, viruses and bacteria, enabling highly precise targeting of disease. Yet their reach has long been limited to the outside of cells. A longstanding goal has been to bring that same precision inside the cell, where many diseases begin. A new study introduces a way to do exactly that, opening the door to therapies aimed at conditions such as Alzheimer’s, Parkinson’s and motor neuron disease.

Antibodies are built from combinations of protein components that form a structure capable of recognizing highly specific targets. They are produced inside cells and then transported out, where they bind to structures on the surface of pathogens or affected cells. This natural design makes them highly effective at targeting threats in the bloodstream or surrounding tissues, but not within cells. Many disease-driving processes occur within cells, including the buildup of harmful proteins in neurodegenerative diseases. Efforts to shrink antibodies into smaller fragments that could function inside cells have faced a major obstacle: once inside, these fragments often lose stability, clump together or break down before they can act.

A solution comes from reengineering antibodies to use only the target-binding portion, allowing that fragment to function inside the cell. This requires adapting them to the intracellular environment, where charge plays a key role in stability and aggregation. Standard antibody fragments often carry a charge that causes them to stick together inside cells rather than move freely. By redesigning these fragments to better match the intracellular environment, more than 600 stable intracellular antibody fragments were created from existing antibodies. These redesigned molecules retain their ability to recognize disease-related targets while operating inside living cells, providing a foundation for therapies that can directly engage the proteins driving neurodegenerative disease.

Antibodies are naturally engineered to work outside cells, not within them. Inside a cell, the environment is chemically different, causing many antibody fragments to misfold, aggregate or degrade before binding their intended targets. A major challenge is electrical charge imbalance, which promotes clumping rather than mobility inside cells.

Adjusting charge distribution allows redesigned fragments to remain stable and functional. Starting from existing antibodies, artificial intelligence was used to modify structures while preserving target recognition. Instead of altering what antibodies bind, the redesign focuses on how they behave inside cells. This creates a modular platform that can be applied across many antibodies. Hundreds of existing antibodies were converted into intracellular versions, enabling rapid adaptation for new uses.

A New Route for Neurodegenerative Disease

The strongest immediate impact may be in diseases driven by protein misfolding and toxic protein buildup inside cells. In conditions such as Alzheimer’s, Parkinson’s, Huntington’s disease and motor neuron disease, abnormal proteins accumulate and disrupt normal cellular function. These harmful changes often occur within the cell, making them difficult to address with traditional antibody therapies.

Intracellular antibody fragments offer a way to directly recognize and bind these harmful protein forms at the site of damage. Because the platform preserves the recognition properties of the original antibodies, it can distinguish between normal and abnormal protein states with high precision. This level of selectivity is especially important in neurodegenerative diseases, where targeting the wrong protein form could disrupt normal cellular function.

The approach also aligns with emerging gene-based delivery technologies, where cells can be directed to produce the antibody fragment themselves. This opens a path toward highly targeted intracellular treatments for diseases that currently have few effective options.

Artificial intelligence plays a central role in making this possible on a larger scale. Once the key design rule around charge was identified, AI-based protein redesign was used to improve stability while preserving target recognition, allowing the rapid conversion of hundreds of antibody sequences into intracellular-ready formats. This step introduces a repeatable engineering framework for the redesign of biologics.

This modular approach is particularly valuable in biotechnology, where platforms applicable across multiple disease areas have strong long-term potential. A system that can convert existing antibodies into intracellular tools could have applications far beyond neurodegenerative disease, including cancer biology, inflammatory disorders and rare genetic conditions.

Changing where antibodies can operate expands the range of biological processes that can be targeted. Existing molecules that were previously limited in their ability to enter cells may now be repurposed as intracellular therapeutics and research tools. In a field where time, specificity and scalability are critical, this shift could have profound implications.

The next wave of biologic therapies may no longer stop at the cell surface. With AI-guided intracellular redesign, antibodies are now positioned to target the molecular events at the heart of some of the world’s most devastating diseases.

This work is part of a series demonstrating how modern antibody strategies can be developed to enhance immune responses, with potential applications across a wide range of diseases and therapeutic areas.