Tumor homing-penetrating and nanoenzyme-augmented 2D phototheranostics against hypoxic solid tumors

Tumor microenvironment (TME)-oriented nanomedicine emerges as an efficient routine to greatly improve the efficiency of cancer treatment. The typical feature of hypoxia in TME remains as the main obstacle of many therapeutics like photodynamic therapy. Herein, a specific two-dimensional (2D) phototheranostics (GO-MnO₂@tLyP-1/Ce6, denoted as GMtC) with the function of oxygen self-producing and tumor barrier-breaking was detailed by integrating the nanoenzyme MnO₂ colloids, tumor homing-penetrating peptide tLyP-1 and photosensitizer chlorin e6 (Ce6) to tackle the hypoxic tumors. GMtC was capable to accumulate into the inner of murine mammary 4T1 tumor spheroids (and the depth could be as far as 90 µm) and to relieve the hypoxia state by catalytic decomposition of endogenous H₂O₂ to oxygen, which subsequently enhanced the yield of cytotoxic singlet oxygen under laser irradiation. In vivo dual-modal imaging of magnetic resonance and biofluorescence demonstrated the targeted accumulation and distribution of GMtC in tumor regions, thus facilitating the tumor hypoxia alleviation. Notably, GMtC achieved the highest photodynamic anticancer efficiency against 4T1 tumors without obvious systemic toxicity compared with the non-penetrating and no oxygen-generating counterparts. This study suggests the great promise of GMtC as an endogenous TME-responsive and exogenous laser-triggered theranostic platform against the solid hypoxic tumors. STATEMENT OF SIGNIFICANCE: The hostile tumor hypoxia not only induces the tumor angiogenesis, invasiveness and irreversible metastasis, but also inherently impairs the efficiency of many therapeutic modalities like photodynamic therapy (PDT). Though numerous hypoxia-alleviating strategies based on nanomedicine have been proposed, little attention is paid to the hypoxia-specific transportation barriers. This study develops a type of 2D phototheranostics GMtC against hypoxic solid tumors by integrating the function of tumor homing-penetrating and in situ oxygen-generating. GMtC displays outstanding performance in tumor deep penetration to hypoxia center and generating abundant oxygen in responsive to tumor microenvironment, thus exerting the highest efficiency of PDT against 4T1 mammary tumor. GMtC can be a potent theranostics to treat the solid hypoxic tumors.