Metal‐DNA Nanocomplexes Enhance Chemo‐dynamic Therapy by Inhibiting Autophagy‐Mediated Resistance

Abstract

Chemo‐dynamic therapy (CDT) based on the Fenton or Fenton‐like reaction has emerged as a promising approach for cancer treatment. However, autophagy‐mediated self‐protection mechanisms of cancer cells pose a significant challenge to the efficacy of CDT. Herein, we developed metal‐DNA nanocomplexes (DACs‐Mn) to enhance CDT via DNAzyme inhibition of autophagy. Specifically, Mn‐based catalyst in DACs‐Mn was used to generate highly hydroxyl radicals (⋅OH) that kill cancer cells, while the ATG5 DNAzyme incorporated into DACs‐Mn inhibited the expression of autophagy‐associated proteins, thereby improving the efficacy of CDT. By disrupting the self‐protective pathway of cells under severe oxidative stress, this novel approach of DACs‐Mn was found to synergistically enhance CDT in both in vitro and in vivo models, effectively amplifying tumor‐specific oxidative damage. Notably, the Metal‐DNA nanocomplexes can also induce immunogenic cell death (ICD), thereby inhibiting tumor metastasis. Specifically, in a bilateral tumor model in mice, the combined approach of CDT and autophagy inhibition followed by immune checkpoint blockade therapy shown significant potential as a novel and effective treatment modality for primary and metastatic tumors.

Enzyme Core Spherical Nucleic Acid That Enables Enhanced Cuproptosis and Antitumor Immune Response through Alleviating Tumor Hypoxia

“…Catalase (CAT), a kind of enzyme widely existing in organism, is capable of efficiently catalyzing the release of O 2 from H 2 O 2 , which is an effective means to relieve tumor hypoxia based on endogenous oxygen supply. − However, inherent shortcomings, such as biological instability, limited target specificity, and challenges in biological delivery, have limited the practical utility of natural catalase. To address these limitations, enzyme immobilization and modification strategies have been explored to reduce the sensitivity of natural enzymes to physical parameters such as temperature and pH, thereby increasing their functional efficiency. − Compared to the low efficiency and high cost of nanomaterial-based enzyme immobilization strategies, DNA offers advantages such as high biological safety, strong affinity, and ease of functionalization. − For instance, the Mirkin group introduced the concept of spherical nucleic acids (SNA) as an effective strategy for DNA-based enzyme modification. − However, ensuring reliable enzyme immobilization and protection requires dense DNA modification, which can potentially compromise enzyme activity or even lead to enzyme inactivation if extensive chemical modifications are made at the active sites. − Therefore, the development of a novel method for low-density chemical grafting that can immobilize and protect enzymes without affecting their activity is of practical importance.…”

Polyvalent Aptamer-Functionalized NIR-II Quantum Dots for Targeted Theranostics in High PD-L1-Expressing Tumors

“…Aptamers, often termed “chemical antibodies”, are oligonucleotide sequences with specific recognition capabilities. They offer high binding specificity, strong affinity, ease of synthesis, chemical stability, and low immunogenicity. − The use of aptamer-based surface modifications can effectively improve the biocompatibility of inorganic materials and improve tumor penetration and retention. − However, challenges arise from the small structure of aptamers, leading to potential problems such as weak binding forces and susceptibility to nucleases in vivo. − To this end, we and others developed the simple and efficient rolling circle amplification (RCA) technique to prepare ultralong single chain polyvalent aptamers (pApt) for the increase of binding force and stability, which can effectively overcome the limitations of short DNA strands, such as poor stability, short blood circulation time, and ease of rapid clearance by the body. − Importantly, the programmable nature of these long single-stranded aptamers allows for flexible synthesis by deleting, adding, or swapping sequences. − However, to the best of our knowledge, the utilization of these long single-stranded aptamers as templates for synthesizing water-soluble quantum dots with NIR-II fluorescence and targeting functionalities has not been reported.…”