Intracellular Self‐Assembly Driven Nucleus‐Targeted Photo‐Immune Stimulator with Chromatin Decompaction Function for Robust Innate and Adaptive Antitumor Immunity

Abstract

Efficient nuclear DNA damage and release is highly recommended to improve the photodynamic immunotherapy by eliciting innate immune response yet remains challenging. Herein, an intracellular self-assembly driven nucleustargeted photo-immune stimulator (PIS) with chromatin decompaction function is reported for innate and adaptive antitumor immunity co-activation. The PIS consists of vorinostat (SAHA)-loaded manganese-porphyrin metal-organic framework (Mn (III)-TCPP MOF) with further modification of AS1411 aptamer. The PIS can be efficiently internalized by tumor cells and disassembled under the intracellular overexpressed glutathione (GSH). Notably, the released AS1411 is able to be self-assembled with photosensitizer TCPP in situ within cells, driving nucleus-targeted delivery of TCPP; meanwhile, the loaded SAHA can induce chromatin decompaction, cooperatively promoting TCPP-mediated photodynamic nuclear DNA damage and cytosolic release under laser irradiation. In addition, the released manganese ions (Mn 2+ ) further enhance the cytosolic DNA/cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway mediated innate immunity, which synergizes with PDT-induced immunogenic cell death to achieve co-activation of innate and adaptive immunity. Compared to traditional PDT, the self-assembly driven nucleus-targeted PDT system with chromatin decompaction show significantly enhanced efficacy for inhibiting primary tumor growth and distant metastasis in several xenograft tumor models, mechanistically by promoting the maturation of dendritic cells and tumor infiltration of natural killer cell, cytotoxic T lymphocytes.

Cascade-activatable NO release based on GSH-detonated “nanobomb” for multi-pathways cancer therapy

“…Currently, increasing emphasis is being placed on the use of certain stress agents that might elicit ICD in tumor cells [ 47 ]. Recent studies have shown that PDT can elicit an adaptive immune response by inducing ICD, thereby expanding the mechanism of PDT in clinical therapy [ 48 ]. It is necessary to explore whether the oxidative stress caused by PDT-GT drives immunological responses of tumor cell immunogenicity.…”

An Overview of Recent Advancements on Manganese-Based Nanostructures and Their Application for ROS-Mediated Tumor Therapy

“…Shi et al developed an intracellular self-assembly driven nuclear-targeted and harmless switchable photoimmunostimulator (PIS) composed of a vorinostat (SAHA)-loaded Mn-porphyrin MOF (Mn (III)-TCPP MOF) and further surface modification composition of PEI and AS1411 aptamers. 178 Benefiting from the quenching effect of Mn (III) on TCPP, PIS exhibited low phototoxicity during blood circulation. AS1411 could promote the uptake of PIS by tumor cells through active targeting, and then PIS was decomposed into Mn 2+ , TCPP, SAHA and AS1411 under the action of intracellular GSH.…”

“…By constructing an in vivo bidirectional 4T1 tumor model and an antimigration model, it was demonstrated that the synthesized MnO x NSs could effectively inhibit primary/distal tumor growth and tumor metastasis (Figure c). Shi et al developed an intracellular self-assembly driven nuclear-targeted and harmless switchable photoimmunostimulator (PIS) composed of a vorinostat (SAHA)-loaded Mn-porphyrin MOF (Mn (III)-TCPP MOF) and further surface modification composition of PEI and AS1411 aptamers . Benefiting from the quenching effect of Mn (III) on TCPP, PIS exhibited low phototoxicity during blood circulation.…”

An assembly-inducing PDC enabling the efficient nuclear delivery of nucleic acid for cancer stem-like cell suppression

“…Many studies have revealed that the electrostatic interactions between short nucleic acids (such as siRNA or DNA aptamers) and cell penetrating peptides or amphiphilic peptides can promote the formation of a stable complex and cellular uptake. [25][26][27][28][29][30] Thus, PDCs can also take advantage of positively charged peptides to achieve nucleic acid drug delivery through DNA-peptide selfassembly by electrostatic interactions. As a result, remarkable synergistic effects of nucleic acid drugs and PDC on cancer proliferation inhibition are observed.…”