‘Mito-Bomb’: a novel mitochondria-targeting nanosystem for ferroptosis-boosted sonodynamic antitumor therapy

Abstract

Mitochondria play an important role in regulating tumor cell death and metabolism so that they can be potential therapeutic targets. Sonodynamic therapy (SDT) represents an attractive antitumor method that induces apoptosis by producing highly toxic reactive oxygen species (ROS). Mitochondria-targeting SDT can cause oxidative damage and improve the efficiency of tumor therapy. However, due to the nonselective distribution of nanosystems and the anti-apoptotic mechanism of cancer cells, the therapeutic effect of SDT is not ideal. Therefore, we proposed a novel mitochondria-targeting nanosystem (‘Mito-Bomb’) for ferroptosis-boosted SDT. Sonosensitizer IR780 and ferroptosis activator RSL-3 were both encapsulated in biocompatible poly(lactic‐ co ‐glycolic acid) (PLGA) nanoparticles to form ‘Mito-Bomb’ (named IRP NPs). IR780 in this nanosystem was used to mediate mitochondria-targeting SDT. RSL-3 inhibited the activity of GPX4 in the antioxidant system to induce ferroptosis of tumor cells, which could rewire tumor metabolism and make tumor cells extremely sensitive to SDT-induced apoptosis. Notably, we also found that RSL-3 can inhibit hypoxia inducible factor-1α (HIF-1α) and induce ROS production to improve the efficacy of SDT to synergistically antitumor. RSL-3 was applied as a ‘One-Stone-Three-Birds’ agent for cooperatively enhanced SDT against triple-negative breast cancer. This study presented the first example of RSL-3 boosting mitochondria-targeting SDT as a ferroptosis activator. The ‘Mito-Bomb’ biocompatible nanosystem was expected to become an innovative tumor treatment method and clinical transformation.

Nanotechnology-enabled sonodynamic therapy against malignant tumors

“…17 are getting a lot of attention, which has greatly changed the concept of traditional disease treatment. [18][19][20] They are dened as submicron-sized (<1 mm) colloidal particles. It is well known that the size of NPs has a great inuence on their therapeutic activity, which can signicantly inuence the mechanism and rate of cell internalization.…”

Tumor Microenvironment‐Related Sonodynamic Therapy Mediates Tumor Therapy

“…On the one hand, ST can reduce the internal glucose of tumors and reduce the energy source of tumor cells. CAT and CAT-like activity Au-rGO-ZnO@PVP, PMR, PEBVO@PEGNRS, Bac@ARS, SPNC, PB+Ce6@Hy, Ce6-MnO 2 -PVs, YHM, Cu 2 O-CNX@CeO 2 , CAT@HA-HMME NPs [51,53,54,156,157,158,159,160,161,162] Consumption of GSH AIMP [163] Catalytic CDT Mn 3 O 4 /OCN-PPIX@BSA, G-IrTe 2 [164,165] Suppress GSH generation BMP-BSO [166] Consumption of GSH, catalytic CDT UPFB, mZMD NCs, MO@FHO, AIPH@Cu-MOF [52,55,84,85] Consumption of GSH, catalytic ST CPCs@PEG [167] Reverse immunosuppression HABT-C@HA, MFC [168,169] Catalytic ST PPGE NCs [50] Consumption of GSH, catalytic CDT, catalytic ST MPG [170] pH-response DOX@PCN-224/Pt NPs [171] Carry oxygen Reverse immunosuppression TL@HPN(PAI/USI), DMXAAS [172,173] ICG-DOX NPs/PFH@SP94-Lip, SAFE [174,175] Autogeneration of oxygen Chl (MChl) [176] Reduce HIF-1𝛼 M@C [73] Reduce HIF-1𝛼 Relieve hypoxia P-BTO [71] IR780@INPS-CTX, IRP-NPs [177,178] Hypoxia-response ZTC, MCA, C-TiO 2 /TPZ@CM [77,179,180] Catalytic CDT Cu-MOF NPs [75] CAT activity hMVS [78] On the other hand, the produced H 2 O 2 can be used as the substrate of CDT and catalase to catalyze the formation of ROS and oxygen. [56]…”

Laser-activated nanoparticles for ultrasound/photoacoustic imaging-guided prostate cancer treatment

“…As a derivative of indocyanine green, IR780 has been confirmed to have good photothermal properties. Meanwhile, it can also be used for photoacoustic (PA) imaging ( Song et al, 2019 ; Li et al, 2021 ; Ren et al, 2021 ; Wang et al, 2022 ). PA imaging is a new type of non-invasive, non-radioactive imaging method emerging in recent years ( Zackrisson et al, 2014 ; Steinberg et al, 2019 ).…”