Tumor microenvironment-responsive nanohybrid for hypoxia amelioration with photodynamic and near-infrared II photothermal combination therapy

Phototherapy, particularly photothermal therapy (PTT) and photodynamic therapy (PDT), has been widely investigated for tumor treatment. However, the limited tissue penetration depth of light in the near-infrared I (NIR-I) region and the hypoxic tumor microenvironment (TME) severely constrain their clinical applications. To address these challenges, in the present study, we developed a chlorin e6 (Ce6) and MnO 2 -coloaded, hyaluronic acid (HA)-coated single-walled carbon nanohorns (SWNHs) nanohybrid (HA-Ce6-MnO 2 @SWNHs) for PDT and PTT combination therapy of tumor. HA-Ce6-MnO 2 @SWNHs responded to the mild acidic TME to ameliorate tumor hypoxia , thus enhancing tumor PDT. Moreover, HA-Ce6-MnO 2 @SWNHs had a high photothermal conversion efficiency at 1064 nm (55.48%), which enabled deep tissue penetration (3.05 cm) and allowed for highly efficient tumor PTT in near-infrared II (NIR-II) window. PDT and PTT combination therapy with HA-Ce6-MnO 2 @SWNHs achieved a good therapeutic efficacy on 4T1 tumor-bearing mice, eradicating the primary tumors and suppressing cancer recurrence. Our study provides a promising strategy for developing a hypoxia relief and deep tissue penetration phototherapy platform by using SWNHs for highly effective tumor PDT and NIR-II PTT combination therapy. Statement of Significance The hypoxic tumor microenvironment (TME) and the limited penetration of the NIR-I light in biological tissues compromise the efficacy of photothermal therapy (PTT) and photodynamic therapy (PDT) on tumors. Here, we developed a chlorin e6 (Ce6) and MnO 2 -coloaded, hyaluronic acid (HA)-coated single-walled carbon nanohorns (SWNHs) nanohybrid (HA-Ce6-MnO 2 @SWNHs) for PDT and PTT combination therapy of tumors. The nanohybrid could efficiently accumulate in tumors through CD44-mediated active targeting. The sequential MnO 2 -enhanced PDT and efficient NIR-II PTT had a remarkable therapeutic effect by eliminating the primary tumor and simultaneously inhibiting tumor recurrence.