RNA G‐Quadruplex–Mediated Solubilization and Photodynamic Activation of Protoporphyrin IX

Abstract

Protoporphyrin IX (PpIX) is a key endogenous photosensitizer used in photodynamic diagnosis (PDD) and photodynamic therapy (PDT); however, its poor aqueous solubility and strong aggregation markedly suppress fluorescence emission and singlet oxygen ( 1 O 2 ) generation. The mechanisms by which PpIX is solubilized intracellularly and becomes photodynamically active remain unclear. PpIX is predominantly produced in mitochondria, where mitochondrial DNA encodes numerous potential G‐quadruplex (GQ)‐forming sequences that can be transcribed into RNA. Although DNA GQs interact with porphyrins, the role of RNA GQs in intracellular PpIX solubilization remains largely unexplored. Here, we investigated the interaction of PpIX with DNA and RNA GQs and evaluated their ability to solubilize PpIX and restore its photodynamic activity using steady‐state and time‐resolved spectroscopic techniques. Incubation of aggregated PpIX with pre‐formed DNA or RNA GQs induced pronounced dispersion and solubilization, accompanied by the appearance of well‐defined Soret and Q bands and substantial fluorescence enhancement. Time‐resolved 1 O 2 luminescence measurements revealed efficient 1 O 2 generation from GQ‐bound PpIX, with apparent quantum yields of 0.17 and 0.10 for DNA‐GQ– and RNA‐GQ–bound PpIX, respectively. These results demonstrate that RNA GQs can function as effective endogenous solubilizing platforms for PpIX, providing new insights into the molecular basis of PpIX‐based PDD and PDT.