Nanopore-confined photosensitizer in metal-organic frameworks enable enhanced multi-responsive photodynamic activities for efficient tumor cell elimination.

Understanding the interaction between photosensitizers and nanocarriers is essential for optimizing photodynamic therapy (PDT), particularly to improve photosensitizer loading efficiency, stability, controlled release, and to modulate its photophysical properties and catalytical activity. Metal-organic frameworks (MOFs), with their nanoconfined pores and high surface areas, offer a promising platform for photosensitizer encapsulation. In this study, we developed a tumor-targeted nano-assembly by encapsulating a hypocrellin-based photosensitizer (HB4) within the NH2-MIL-101(Fe) MOF, followed by surface modification with polyethylene glycol (PEG) and folic acid (FA) to obtain HB4/FA-PEG@MOF. This multifunctional system exhibited tumor microenvironment (TME)-responsive catalytic activity, enabling the efficient generation of hydroxyl radicals (•OH) and superoxide radical anions (O2•-), which triggered potent anticancer effects by inducing mitochondrial membrane depolarization, along with extensive damage to cellular lipids and proteins. Synchrotron radiation-based small angel X-ray scattering (SR-SAXS) analysis confirmed that HB4 was confined within the {111} facet pores of the MOF, which facilitated electron transfer to O2 to generate O2•- and TME responsiveness. The study clearly elucidated the precise spatial configuration of the photosensitizers (PSs) confined within the MOF pores, which provides a mechanistic interpretation of the structure-activity relationship.