Engineered DNA frameworks have been extensively exploited as affinity scaffolds for drug delivery. However, few studies focus on the rational design to comprehensively improve their stability, internalization kinetics, and drug loading efficiency. Herein, DNA framework‐based hybrid nanomaterials are rationally engineered by using a molecular docking tool, where the framework acts as a template to support conjugated polymers. The hybrid materials exhibit high stability in biofluids owning to the multiple interactions between DNA and cationic conjugated polymer. Through molecular docking, it is found that a specific structure of the conjugated polymer at major grooves of DNA gives rise to a unique pocket for small‐molecular drug doxorubicin (DOX) yielding lower binding energy than conventional DOX binding sites. This increases the binding affinity of DOX, allowing for high drug loading content and efficiency, and preventing drug leakage under physiological condition. As a proof of concept, the hybrid nanomaterials equipped with aptamer are used to carry DOX and antisense oligonucleotide G3139, which effectively inhibits solid tumor growth and shows negligible side effects on mice. It is anticipated that this approach would find broad applications in hybrid materials design and precise medicine.

In this contribution, we report a unique co-assembly composed of pyrene and spiropyran that were linked separately at the focal point of the same peptide-based dendron (Phe-Glu), in which the dendrons offer driving forces for the coaggregation. A series of co-assemblies with different weight ratios (Py-Phe-Glu/SP-Phe-Glu) were prepared and the morphology could be tuned. It is found that the resulting stable co-assembled organogel is double switchable triggered by light and heat. TEM revealed that, in the xerogel, Py-Phe-Glu formed rigid rod nanofibers with large diameters and acted as a rigid sketelon where the gracile interwoven fibrous structure of SP-Phe-Glu grew. More interestingly, the original powder of the co-assembled xerogel (1.0 mg/0.1 mg) not only displayed a sequential high-contrast tricolored switch from dark blue to bright cyan and to red under external force but also presented multistate accessible photochromic properties. Such mechanochromic and photochromic behaviors of the xerogel are mainly due to the transition of different excimers of pyrene and the force/photoinduced ring-opening reaction of spiropyran. It is rarely reported that self-assembled soft materials achieve mechanochromic and photochromic dual-responsive behaviors with a high-contrast multicolored switch. We believe the co-assembly strategy based on polypeptide dendrons can be extended to other systems for establishing novel intelligent fluorescent materials.

Graphical Abstract

Single nucleotide variant (SNV) has become an emerging biomarker for various diseases such as cancers and infectious diseases. Toehold-mediated strand displacement (TMSD), the core reaction of DNA nanotechnology, has been widely leveraged to identify SNVs. However, inappropriate choice of mismatch location results in poor discrimination ability. Here, we comprehensively investigate the effect of mismatch location on TMSD kinetics by molecular dynamic simulation tool oxDNA through umbrella sampling and forward flux sampling disclosing that mismatches at the border of the toehold and branch migration domain yield the lowest TMSD reaction rate. Nine disease-related SNVs (SARS-CoV--DG, EGFR-LR, EGFR-TM, KRAS-GR, etc.) were tested experimentally showing a good agreement with simulation. The best choice of mismatch location enables high discrimination factor with a median of 124 for SNV and wild type. Coupling with a probe-sink system, a low variant allele frequency of 0.1% was detected with 3 S/N. We successfully used the probes to detect SNVs with high confidence in the PCR clones of constructed plasmids. This work provides mechanistic insights into TMSD process at the single-nucleotide level and can be a guidance for the design of TMSD system with fine-tuning kinetics for various applications in biosensors and nanotechnology.

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