Activatable Enzymatic Nanoplatform Incorporated into Microneedle Patch for Relieving Tumor Hypoxia Augmented Photodynamic Therapy

Abstract The clinical advancement of photodynamic therapy (PDT) faces entrenched impediments, particularly the suboptimal solubility of hydrophobic photosensitizers (PSs) and tumor‐associated hypoxia. Herein, a universally applicable, carrier‐free nanotherapeutic platform is devised in which catalase (CAT) functions dually as a biocatalytic oxygenator and a biocompatible scaffold for PSs encapsulation. Through self‐assembly with diverse hydrophobic PSs—including 2‐(1‐hexyloxyethyl)‐2‐divinyl‐pyropheophorbide‐a (HPPH), chlorin e6 (Ce6), and zinc (II)‐phthalocyanine (ZnPc)—CAT forms uniform and stable PS@CAT nanoparticles (NPs), obviating the necessity for supplementary nanocarriers. These nanostructures are embedded within microneedle (MN) patches, facilitating minimally invasive, spatially targeted transdermal administration. The PSs bind to the hydrophobic pocket of CAT within NPs, temporarily suppressing its bioactivity, which is restored upon NPs disassembly in the acidic tumor microenvironment (TME). This pH‐responsive “OFF‐to‐ON” mechanism orchestrates the synchronized release of PSs and reactivation of CAT, which catalyzes endogenous hydrogen peroxide (H₂O₂) to generate oxygen (O 2 ), alleviating hypoxia and augmenting O 2 availability for PDT. In vivo validation in a 4T1 murine mammary carcinoma model corroborated this approach's therapeutic superiority and biocompatibility. Collectively, the findings delineate a minimalist, multifunctional strategy to simultaneously enhance the bioavailability of PSs and overcome hypoxia in PDT for more efficacious oncologic therapy.