Integrated Nanorod‐Mediated PD‐L1 Downregulation in Combination with Oxidative‐Stress Immunogene Therapy against Cancer

Abstract

It is an engaging program for tumor treatment that rationalizes the specific microenvironments, activation of suppressed immune system (immune resistance/escape reversion), and synergistic target therapy. Herein, a biomimetic nanoplatform that combines oxidative stress with genetic immunotherapy to strengthen the therapeutic efficacy is developed. Ru‐TePt nanorods, small interfering RNA (PD‐L1 siRNA), and biomimetic cellular membrane vesicles with the targeting ability to design a multifunctional Ru‐TePt@siRNA‐MVs system are rationally integrated. Notably, the Fenton‐like activity significantly enhances Ru‐TePt nanorods sonosensitization, thus provoking stronger oxidative stress to kill cells directly. Meanwhile, immunogenic cell death is triggered to secrete numerous cytokines and activate T cells. The effective catalase characteristics of Ru‐TePt enable the in situ oxygen‐producing pump to improve tumor oxygen level and coordinately strengthen the therapeutic effect of SDT followed. More importantly, anti‐PD‐L1‐siRNA mediated immune checkpoint silence of the PD‐L1 gene creates an environment conducive to activating cytotoxic T lymphocytes, synergistic with boosted reactive oxygen species‐triggered antitumor immune response. The experimental results in vitro and in vivo reveal that the Ru‐TePt@siRNA‐MVs nanosystems can effectively activate the oxidative stress‐triggered immune response and inhibit PD‐1/PD‐L1 axis‐mediated immune resistance. Consequently, this orchestrated treatment paradigm provides valuable insights for developing potential oxidative stress and genetic immunotherapy.

Nanomaterials augmented bioeffects of ultrasound in cancer immunotherapy

“…In another example, a strategy of encapsulating Ru–TePt and PD-L1 siRNA by biomimetic cell membrane vesicles expressing transferin realized the multifunctional integration of CDT-SDT-gene therapy-immunotherapy, which effectively induced the activation of adaptive immunity [ 173 ]. Ru–TePt acted as a charge trap to hinder the recombination of electron-hole (e − -h + ), generated •OH and 1 O 2 , and enhance the efficiency of SDT.…”

Tumor Microenvironment‐Related Sonodynamic Therapy Mediates Tumor Therapy

“…[101][102][103] The interaction between tumor cells and immune cells in the TME determines the immune state of the TME during tumor growth. [104] In the early stage of tumor growth, effector T cells (including the cluster of differentiation (CD8 + T cells), cytotoxic T cells, and effector CD4 + T cells), macrophage phenotype 1 (M1), and NK cells can cooperatively inhibit the occurrence Induce ICD Promote the maturation of DCs Zr-TCPP(TPP)/R837@M, PMPS NDs, AMR-MOF@AuPt [112,198,199] Promote the maturation of DCs, combined ICB Ru-TePt@siRNA-MVs, CPDA@PFH [113,114] Promote the maturation of DCs and NKs 195/Ce6-NBs [200] Promote the maturation of DCs, reduce Tregs cTiSe 2 NS, QDs [111,201] Combined ICB, and catalytic CDT, relieve hypoxia IRO@FA NP [202] Combined chemotherapy Doxo [203] Hyp [204] TAMs related Promote the transformation of M2 into M1, promote the maturation of DCs M1/IR780@PLGA [205] Targeted removal of M2, vascular normalization, and relief hypoxia M-H@lip-ZA [206] and growth of the tumor, and the TME shows a state of immune promotion. With the development of cancer, in the late stage of tumor growth, the TME mainly contains Tregs, M2 macrophages, and immature DCs, showing a tumor-promoting effect, and the TME presents an immunosuppressive state.…”

“…ICD induction can further improve the response of T cells to tumor cells (Figure 6fj). [113,114] SDT combined with immunotherapy can effectively improve the effect of synergistic antitumor immunotherapy. SDT can effectively induce ICD by promoting the release of TAAs, changing the immunosuppressive state of the TME, and effectively promoting the effect of antitumor immunotherapy.…”

Cationic Polythiophene as Gene Carrier and Sonosensitizer for Sonodynamic Synergic Gene Therapy of Hepatocellular Carcinoma

“…Wu et al developed a versatile Ru-TePt@siRNA-MVs platform with tumor-targeting properties. This system is composed of siRNA (PD-L1 siRNA), Ru-TePt nanorods, and biomimetic cellular membrane vesicles and has intelligent targeting abilities . Although the above examples show the combination of SDT and gene therapy, the SDT-induced hypoxic tumor microenvironment can decrease the ROS generation efficiency in the later stage of SDT treatment .…”