Data-Efficient Active Learning Discovery of Transition Metal Photosensitizers for Type I Photodynamic Therapy

TL;DR

This paper introduces a data-efficient active learning framework to discover transition-metal complexes as photosensitizers for Type I photodynamic therapy, significantly reducing computational effort while revealing key chemical design principles.

Contribution

The study develops a novel active learning approach combining targeted DFT and atomistic representations to efficiently identify promising TMC photosensitizers from a vast chemical space.

Findings

Enriched candidates within a specific redox region using only 300 quantum-chemical evaluations.

Identified Os(II)-based complexes as particularly effective for Type I photoreactivity.

Revealed chemical design principles linking metal, ligand, and substituents to photoreactivity.

Abstract

Transition-metal complexes (TMCs) are promising photosensitizers for Type~I photodynamic therapy (PDT), where electron-transfer processes can generate reactive oxygen species under hypoxic conditions. Yet identifying candidates with the required ground- and excited-state redox energetics remains challenging across the vast chemical space of TMCs. Here, we develop a data-efficient active learning (AL) framework for the discovery of Type~I active TMC photosensitizers by combining a chemically structured design space of over 2.1 million Ru(II), Os(II), and Ir(III) complexes with targeted DFT calculations and pretrained atomistic representations. With only 300 quantum-chemical evaluations, the approach efficiently enriches candidates within a mechanistically defined optimal redox region. Analysis of the viable complexes reveals chemical design principles linking metal identity, ligand framework, substituent pattern, and physicochemical properties to Type~I photoreactivity, including a pronounced preference for Os(II)-based complexes and electronically asymmetric ligand environments along with combination of electronic donating and accepting substituents. More broadly, the strategy presented herein provides a scalable, mechanism-guided route for the rational design of transition-metal photocatalysts for applications spanning biomedicine, solar energy conversion, and photoredox chemistry.