Multifunctional nanoplatform for tumor chemodynamic and self-amplified photodynamic cascade therapy

• Developed 5-ALA@Zn-CuTz@PM nanoparticles with platelet membrane modification, enabling efficient breast cancer targeting and combined PDT/CDT for enhanced tumor inhibition. • Zn 2+ -induced Zn-PpIX formation inhibits HO-1, increases intratumoral PpIX, while Cu + generates hydroxyl radicals from H 2 ​O 2 ​, boosting PDT/CDT synergy. • Luminescence tracking confirmed tumor-specific accumulation and biodistribution of nanodrugs, highlighting excellent targeting efficiency. • Demonstrated enhanced PDT/CDT effects with strong biocompatibility and negligible toxicity to major organs. • H&E staining and biomarker quantification (HO-1, heme, bilirubin) revealed therapeutic mechanisms and ensured safety at the tissue level. 5-Aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT) has demonstrated considerable potential in breast cancer treatment. However, its efficacy is limited by low tissue selectivity and the rapid conversion of 5-ALA to non-photosensitive heme in tumor tissues, reducing its therapeutic effectiveness. This study aims to develop a multifunctional nanomedicine to enhance 5-ALA’s PDT efficacy while introducing chemodynamic therapy (CDT) for synergistic tumor inhibition. By designing a zinc-ion-doped cuprous metal–organic framework (MOF) nanocarrier loaded with 5-ALA (5-ALA@Zn-CuTz), we seek to improve tumor targeting, prolong photosensitizer retention, and enhance therapeutic outcomes. To enhance biocompatibility and active tumor targeting, the surface of 5-ALA@Zn-CuTz nanoparticles (NPs) was modified with a platelet membrane (PM), forming 5-ALA@Zn-CuTz@PM NPs. The therapeutic efficacy was evaluated in vitro and in vivo using mice breast cancer models. Cellular uptake, reactive oxygen species (ROS) generation, and tumor inhibition efficiency were analyzed through fluorescence imaging, biochemical assays, and histological analysis. Upon intravenous administration, 5-ALA@Zn-CuTz@PM NPs selectively accumulated in breast cancer cells. Within the tumor, Zn 2+ bound to intracellular protoporphyrin IX (PpIX) to form PpIX-Zn, inhibiting heme oxygenase-1 (HO-1) activity and preventing the conversion of PpIX into heme. This increased the effective intracellular concentration of the photosensitizer, thereby enhancing PDT. Additionally, Cu + catalyzed the decomposition of excess H 2 O 2 in the tumor microenvironment, generating oxygen and hydroxyl radicals, which alleviated hypoxia and activated CDT. The synergistic PDT/CDT effect significantly enhanced tumor growth inhibition in vitro and in vivo. 5-ALA@Zn-CuTz@PM NPs effectively enhance PDT efficacy through selective tumor targeting and HO-1 inhibition while simultaneously leveraging CDT for additional tumor suppression. The combined PDT/CDT strategy demonstrated superior therapeutic outcomes, highlighting the potential of this nanoplatform as a promising approach for breast cancer treatment.