Traceable Lactate-Fueled Self-Acting Photodynamic Therapy against Triple-Negative Breast Cancer

The depth of light penetration and tumor hypoxia restrict the efficacy of photodynamic therapy (PDT) in triple-negative breast cancer (TNBC), while the overproduction of lactate (LA) facilitates the development, aggressiveness, and therapy resistance of TNBC. To address these issues, a self-acting PDT nanosystem (HL@hMnO₂-LOx@HA) is fabricated by loading 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-alpha (HPPH), luminol, and LA oxidase (LOx) in a hyaluronic acid (HA)-coated hollow manganese dioxide (hMnO₂) nanoparticle. LOx catalyzes the oxidation of LA into pyruvate and hydrogen peroxide (H₂O₂), thus depleting the overproduced intratumoral LA. In the acidic tumor microenvironment, H₂O₂ reacts with luminol and hMnO₂ to yield blue luminescence as well as O₂ and Mn²⁺, respectively. Mn²⁺ could further enhance this chemiluminescence. HPPH is then excited by the chemiluminescence through chemiluminescence resonance energy transfer for self-illuminated PDT. The generated O₂ alleviates the hypoxia state of the TNBC tumor to produce sufficient ¹O₂ for self-oxygenation PDT. The Mn²⁺ performs T ₁ magnetic resonance imaging to trace the self-acting PDT process. This work provides a biocompatible strategy to conquer the limits of light penetration and tumor hypoxia on PDT against TNBC as well as LA overproduction.