# Machine Learning‐Informed Nano Co‐Assembly Inhibits Fibroblast Activation Protein and Improves Drug Delivery in Fibrotic Tissue

## TL;DR

A new nanoparticle platform using a FAP inhibitor improves drug delivery in fibrotic tissues by overcoming biological barriers.

## Contribution

SP-13786 is introduced as a universal excipient for co-assembly nanoparticles with insights from machine learning and molecular simulations.

## Key findings

- SP-13786 enables stable co-precipitation of diverse hydrophobic drugs into nanoparticles.
- Machine learning and simulations reveal key factors for nanoparticle assembly and stability.
- SCAN nanoparticles improve drug delivery and therapeutic outcomes in fibrotic disease models.

## Abstract

Nanoparticle‐based drug delivery faces persistent challenges, including complex fabrication processes and limited lesional accumulation. Here we introduce SP‐13786 (SP), a precise small‐molecule inhibitor of fibroblast activation protein (FAP), as a universal and effective excipient enabling facile co‐precipitation into stable nanoparticles (SCAN) with diverse hydrophobic drugs. Screening of 861 compounds revealed a broadly enhanced colloidal stability and drug loading by SP. Corresponding simulations and explainable machine learning (XML) showed SCAN assembly hinges on balanced aromaticity, rigidity, and nitrogen‐mediated interaction, offering interpretable framework for co‐assembly nanomedicine. Biological assessment demonstrate that SCAN enhances drug delivery and therapeutic efficacy in FAP‐positive cells, therefore attentuate the fibrosis‐induced drug penetration barriers, increasing drug accumulation within the fibrotic tissue. The improved bioavailability correlate with superior therapeutic outcomes in multiple disease models with progressive fibrosis. Overall, we establish SP as a versatile nanotherapeutic platform combining simplicity in preparation, mechanistic insights provided by XML, and broad applicability for diseases characterized by pathological fibrosis and impaired drug delivery.

We present SP‐13786 (SP), a fibroblast activation protein (FAP) inhibitor, as a universal excipient for co‐assembling stable drug nanoparticles (SCAN). Assembly mechanism deciphered by molecular dynamics and explainable machine learning, SCAN attenuate fibrosis‐induced stromal barriers, enhances lesional drug accumulation, and improves therapeutic efficacy across diverse disease models with a simple and broadly applicable formulation strategy.