Metal-organic cage-mediated synergistic tumor microenvironment remodeling and self-enhanced photodynamic therapy.

Photodynamic therapy (PDT) is a promising non-invasive antitumor strategy, but its clinical efficacy is severely hampered by two critical bottlenecks: aggregation-caused quenching (ACQ) of photosensitizers (PSs) and the hypoxic tumor microenvironment (TME). Herein, we rationally construct a multifunctional nanoplatform (PFD@FeZn@PEG) based on a porphyrin-derived metal-organic cage (MOC) for self-boosting synergistic PDT. The rigid framework of the FeZn MOC spatially isolates porphyrin monomers, efficiently suppressing π-π stacking and ACQ to retain robust singlet oxygen (1O2) generation capacity under laser irradiation. Meanwhile, the hydrophobic internal cavity of FeZn MOC enables stable encapsulation of the antifibrotic drug pirfenidone (PFD) via non-covalent host-guest interactions, forming a 1:1 complex with a binding constant (Kₐ) of 1.23 × 104 M-1 and achieving sustained drug release (≈ 82% within 24 h) under tumor microenvironment conditions. In vivo antitumor studies demonstrate that PFD released in situ remodels TME by downregulating hyaluronic acid and type I collagen expression, normalizing tumor vasculature, improving intratumoral oxygen perfusion and contributing to amplified PDT. This work provides a novel paradigm for the rational design of integrated MOC-based nanosystem, offering a clinically translatable strategy to overcome the limitations of conventional PDT for solid tumor treatment.