Photodynamic therapy (PDT) is a therapeutic strategy that is dependent on external light irradiation that faces a major challenge in cancer treatment due to the poor tissue‐penetration depths of light irradiation. Herein, a DNA nanocomplex that integrates persistent‐luminescence nanoparticles (PLNPs) is developed, which realizes tumor‐site glutathione‐activated PDT for breast cancer without exogenous laser excitation. The scaffold of the nanocomplex is AS1411‐aptamer‐encoded ultralong single‐stranded DNA chain with two functions: i) providing sufficient intercalation sites for the photosensitizer, and ii) recognizing nucleolin that specifically overexpresses on the surface of cancer cells. The PLNPs in the nanocomplex are energy‐charged to act as a self‐illuminant and coated with a shell of MnO2 for blocking energy degradation. In response to the overexpressed glutathione in cancer cells, the MnO2 shell decomposes to provide Mn2+ to catalytically produce O2, which is essential to PDT. Meanwhile, PLNPs are released and act as a self‐illuminant to activate the photosensitizer to convert O2 into cytotoxic 1O2. Significant tumor inhibition effects are demonstrated in breast tumor xenograft models without exogenous laser excitation. It is envisioned that a laser‐excitation‐free PDT strategy enabled by the PLNP–DNA nanocomplex promotes the development of PDT and provides a new local therapeutic approach.

The extreme instability of mRNA makes the practical application of mRNA-based vaccines heavily rely on efficient delivery system and cold chain transportation. Herein, a DNA-based nanomachine, which achieves programmed capture, long-term storage without cryopreservation, and efficient delivery of mRNA in cells, is developed. The polythymidine acid (Poly-T) functionalized poly(N-isopropylacrylamide) (DNA-PNIPAM) is synthesized and assembled as the central compartment of the nanomachine. The DNA-PNIPAM nano-assembly exhibits reversible thermal-responsive dynamic property: when lower than the low critical solution temperature (LCST, ≈32 °C) of PNIPAM, the DNA-PNIPAM transforms into extension state to expose the poly-T, facilitating the hybridization with polyadenylic acid (Poly-A) tail of mRNA; when higher than LCST, DNA-PNIPAM re-assembles and achieves an efficient encapsulation of mRNA. It is remarkable that the DNA-PNIPAM nano-assembly realizes long-term storage of mRNA (≈7 days) at 37 °C. Biodegradable 2-hydroxypropyltrimethyl ammonium chloride chitosan is assembled on the outside of DNA-PNIPAM to facilitate the endocytosis of mRNA, RNase-H mediating mRNA release occurs in cytoplasm, and efficient mRNA translation is achieved. This work provides a new disign principle of nanosystem for mRNA delivery.

Messenger RNA (mRNA) transfection is the prerequisite for the application of mRNA‐based therapeutics. In hard‐to‐transfect cells, such as macrophages, the effective transfection of mRNA remains a long‐standing challenge. Herein, a smart DNA‐based nanosystem is reported containing ribosome biogenesis‐promoting siRNA, realizing efficient mRNA transfection in macrophages. Four monomers are copolymerized to form a nanoframework (NF), including N‐isopropylacrylamide (NIPAM) as the skeleton and acrydite‐DNA as the initiator to trigger the cascade assembly of DNA hairpins (H1‐polyT and H2‐siRNA). By virtue of the phase transition characteristic of polymeric NIPAM, below the lower critical solution temperature (LCST, ≈34 °C), the NF swells to expose polyT sequences to hybridize with the polyA tail of mRNA. Above the LCST, the NF deswells to encapsulate mRNA. The disulfide bond in the NF responds to glutathione, triggering the disassembly of the nanosystem; the siRNA and mRNA are released in response to triphosadenine and RNase H. The siRNA down‐regulates the expression of heat shock protein 27, which up‐regulates the expression of phosphorylated ribosomal protein S6. The nanosystem shows satisfactory mRNA transfection and translation efficiency in a mouse model. It is envisioned that the DNA‐based nanosystem will provide a promising carrier to deliver mRNA in hard‐to‐transfect cells and promote the development of mRNA‐based therapeutics.

No abstract