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.