Functional Nanoscale Therapeutics

Projektinformationen

FunctionalNanoTher

ID Finanzhilfevereinbarung: 101097834

DOI

10.3030/101097834

EK-Unterschriftsdatum 3 November 2023

Startdatum 1 Januar 2024

Enddatum 31 Dezember 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 2 499 796,00

EU-Beitrag

€ 2 499 796,00

Koordiniert durch

UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Ireland

Periodic Reporting for period 1 - FunctionalNanoTher (Functional Nanoscale Therapeutics)

Berichtszeitraum: 2024-01-01 bis 2026-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The project aims to develop therapeutic strategies against currently intractable or inaccessible disease targets where biological barriers block conventional therapies.
The fundamental hypothesis that sparked the project was that there are natural ‘intelligent’ pathways and processes for structures that are used by the body to manage its own valuable natural signals.
By intelligent pathways we means ones where the mechanism that checks access have a ‘synapse' that collects information, surface, architecture and composition of structures that approach them.
A synapse is a membrane interface at or within a cell where information can be collected, and familiar examples are in the brain at neurons, and in the immune system.
These checking mechanisms are very old, and fundamental to life, because such pathways across barriers are highly protected to exclude foreign materials, pathogens and other sources of danger.
Unfortunately they are occasionally taken over, or exploited in disease (for example in tumours). Then the natural protections are turned against us, and make it difficult for treatment to reach the right place.
This is a fundamental challenge for many intractable diseases. Often it means that being blocked from these routes we have to give large doses of drugs to try to force some treatment into the right place, but the extra used also hurts the patient.
Our project aims to understand how these synapses work, and how they may be unbarred to allow therapeutic treatments.Being very old, they have developed over all time of evolution so they are very complex instruments.
Our premise is that, if we unravel and learn how to constructively use them, we would be able to deliver tiny amounts of the right treatment-no excess-to the right place. That understanding and access could then be a platform for practical developments for a new kind of treatment.
Where relevant, the project also engages societal and humanities-linked dimensions: responsible innovation, safety-by-design, and the broader question of how to translate powerful delivery capabilities into ethically governed and publicly trusted medical tools.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The work has progressed in closely cooperative directions: (i) establishing that recognition-gated access programmes exist and can be interrogated, (ii) developing methods to capture and characterise rare, transient interface states, and (iii) reconstructing higher-order organisational rules from complex multi-omic and imaging data.

1) Establishing and validating recognition-gated interface programmes
A key early challenge was that the field lacked broad agreement that complex, synapse-like decision processes operate at these intermediate (“mesoscopic”) scales. We generated evidence that cellular interfaces can distinguish among assemblies based on surface, architecture and composition, and that this recognition can trigger non-default biological routing and trafficking outcomes. Importantly, we obtained convergent validation across readouts (structural, molecular, spatial, and functional), rather than relying on any single class.

2) Building the capability to “catch the process in the act”
The relevant biological material exists in extremely small amounts and often in transient states. Standard workflows in proteomics/transcriptomics and conventional imaging are not designed for this combination of scarcity, spatial specificity, and dynamics. We therefore developed and integrated new workflows for:

- selective recovery of rare mesoscopic populations and interface-associated material;

- spatially resolved molecular identification (proteins and RNAs) compatible with low input;

- time-resolved imaging strategies that link trajectories and fates to molecular states;

- functional tests that confirm that delivered or redistributed biomolecular components remain active rather than merely present.

Inferring organisational “rules” rather than lists of parts

Even with advanced methods and our best efforts to advance them, the resulting datasets resemble a partially observed machine: many components are seen, but the organisational logic must be reconstructed. We therefore applied AI-assisted analysis to detect recurring patterns—co-occurrences, modularity, and state transitions—consistent with a structured “grammar” of recognition and routing. This reframes the system from an accumulation of molecular interactions into a higher-order, interpretable programme that can be learned, tested, and ultimately engineered.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Beyond incremental advances, the project contributes a new conceptual and experimental framework: biological barriers can implement recognition-gated programmes that operate at biological interfaces, and these programmes can be studied systematically and, in principle, harnessed.

Key advances beyond the current state of the art include:

- a practical route to interrogate rare and transient interface decisions using integrated recovery, imaging, and multi-omic identification;

- evidence that particle architectures can encode routing outcomes (not merely uptake efficiency);

- early design logic suggesting that controlled changes to surface/organisation can switch outcomes between degradation versus privileged access routes;

- an explicit bridge between mechanistic biology and modern inference tools: using AI not as a black box, but as a method to reconstruct organisational rules from high-dimensional, partially observed data.

The project is fundamental, and strategic in nature, and seeks to understand how the processes work, and may be harnessed to create a new framing of medicine of ‘hard to address’ disease. Our interest is to advance it quickly, using all the assets and help available from any direction.

Potential impacts

If developed to maturity, the work supports a shift from “dose-based forcing” toward “programme-based access”: therapies designed to cooperate with endogenous gating mechanisms to reach difficult targets with reduced systemic burden.

Key needs for further uptake and success

- deeper quantitative mapping of interface states across more biological contexts (including specific disease-relevant settings);

- working at mesoscopic scales of biology-expanded single-particle/single-event validation to connect molecular organisation to fate with higher precision;

- translational partnerships (clinical, industrial, and regulatory) to guide safety, manufacturability, and deployment;

- early organisation, logistical and planning support to ensure rapid and robust translation while preserving openness where appropriate.

Standardisation, inter-laboratory comparisons and related efforts to assist with widespread acceptance, understanding as well to build to extend the research capacity of organisations that could develop useful specialisations within the field.

This is an intentionally strategic, platform-oriented effort: it aims to reveal and formalise a class of biological access mechanisms that, once understood, can underpin multiple downstream therapeutic directions.