Traceless photodegradable polymer cocoons for universal protein delivery and light-controlled gene editing

Polymer conjugation was found highly valuable in clinic to improve the bioavailability of protein therapeutics.However,it is still a tremendous challenge to achieve a complete release of original proteins from the conjugated hybrid under external stimulus to recover active proteins in the targeted tissue.Herein,we report a general light-controlled protein delivery methodology by weaving a photodegradable polymer cocoon around proteins,which could reliably protect them from degradation in the dark while efficiently releasing them under illumination without any residual atoms.The surface charge of the polymer shell is easily tunable to facilitate efficient cell uptake.The versatility of this strategy is demonstrated by the delivery of the Cas9/sg RNA complex that realized light-controlled gene editing both in vitro and in vivo,and such repertoire is of particular value in regard to minimizing the off-target toxicity of CRISPR-Cas9-based gene therapy.

Programmed albumin nanoparticles regulate immunosuppressive pivot to potentiate checkpoint blockade cancer immunotherapy

The therapeutic efficacy of programmed cell death protein 1/programmed cell death-ligand 1(PD-1/PD-L1)blockade immunotherapy is extremely dampened by complex immunosuppressive mechanisms including regulatory T cells(Treg),M2 macrophages(M2),and prostaglandin E2(PGE2).The pivotal roles of PGE2 have been recognized by directly inactivating CD8+T cells and indirectly inducing Treg and M2.Therefore,PGE2 abolishment through inactivating cyclooxygenase-2(COX-2)could be robust to sensitize tumour toward anti-PD-1/PD-L1 immunotherapy,which has gone into clinical trials.However,exploring this promising strategy in nanomedicine to enhance immunotherapy remains unrevealed.The key challenge to synergistically combine COX-2 inhibition and anti-PD-1/PD-L1 lies in the different pharmacokinetic profiles and the spatial obstacles since PD-1/PD-L1 interaction occurs extracellularly and COX-2 locates intracellularly.Thus,the programmed release nanoparticles(termed as Cele-BMS-NPs)are rationally designed,which are composed of pH-sensitive human serum albumin derivative,BMS-202 compound as PD-1/PD-L1 inhibitor,glutathione(GSH)-activatable prodrug of celecoxib(COX-2 inhibitor).The in vitro experiments demonstrate that this smart Cele-BMS-NPs could extracellularly release BMS-202 under the acidic tumour microenvironment,and the intracellularly release of celecoxib in response to the elevated GSH concentration inside tumour cells.After systemic administration,the intratumoral infiltration of CD8+T cells is significantly enhanced and meanwhile immunosuppressive M2,Treg,and PGE2 are reduced,thereby eliciting the anti-tumour immune responses toward low immunogenic tumours and postsurgical tumour recurrences.

Directional design and synthesis of high-yield hollow Fe-MFI zeolite encapsulating ultra-small Fe_(2)O_(3) nanoparticles by using mother liquid

How to directionally design the hollow zeolite via a green route is of great significance. Here, we successfully synthesized the hollow Fe-silicate-1 encapsulated ultra-small Fe_(2)O_(3) nanoparticles (2.5 nm) with higher yield (85.2%) by mother liquid than traditional dissolution-recrystallization for the first time, which was achieved by precisely regulating the number and distribution of defects in zeolite and cleverly utilizing the TPAOH and nuclei in mother liquor. The effects of synthetic temperature, synthetic period and addition amount of parent zeolite on the formation of hollow zeolite have been investigated and the effect of synthetic conditions on the defects in parent zeolite has been also firstly quantified. The corresponding formation mechanism has been proposed. The abundant inner defects provided by the zeolite synthesized at 130 °C for 1 day and large amount of TPAOH remaining in mother liquid are conducive to the formation of hollow zeolite. Meanwhile, both parent zeolite and nuclei (4-, 5-member rings and structure units) in mother liquid obtained at 130 °C play the crucial roles in enhancing the zeolite yield. Notably, Fe_(2)O_(3) nanoparticles could decompose into small fragments by the interaction with nuclei in mother liquid. Partial ultra-small Fe_(2)O_(3) nanoparticles would be encapsulated in cavity and the rest could be inserted in the zeolite framework, which is significantly different from the conventional dissolution-recrystallization mechanism. The obtained encapsulated catalyst shows the superior catalytic performance and stability in phenol and tetracycline degradation reactions.

DNA origami-based nano-hunter enriches low-abundance point mutations by targeting wild-type gene segments

Point mutations can be used as biomarkers to perform diagnosis for diseases. In this study, a nanorobot for low-abundance point mutation enrichment was constructed using DNA origami. The novel design achieved limits of detection of 0.1% and 1% for synthesized DNA samples and clinical gene samples, respectively. Resettability was a key property of this method, which also involved a simpler process, lower cost and shorter detection duration than traditional enrichment methods. This novel DNA nanorobot may enable the detection of tumor markers, potentially facilitating early cancer diagnosis.