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@hMnO 2 -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 (hMnO 2 ) nanoparticle. LOx catalyzes the oxidation of LA into pyruvate and hydrogen peroxide (H 2 O 2 ), thus depleting the overproduced intratumoral LA. In the acidic tumor microenvironment, H 2 O 2 reacts with luminol and hMnO 2 to yield blue luminescence as well as O 2 and Mn 2+ , respectively. Mn 2+ could further enhance this chemiluminescence. HPPH is then excited by the chemiluminescence through chemiluminescence resonance energy transfer for self-illuminated PDT. The generated O 2 alleviates the hypoxia state of the TNBC tumor to produce sufficient 1 O 2 for self-oxygenation PDT. The Mn 2+ 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.