Cancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity.

Expression of the cell surface receptor CD137 has been shown to enhance anti-cancer T cell function via engagement with its natural ligand 4-1BBL. CD137 ligation with engineered ligands has emerged as a cancer immunotherapy strategy, yet clinical development of agonists has been hindered by either toxicity or limited efficacy. Here we show that a CD137/PD-1 bispecific antibody, IBI319, is able to overcome these limitations by coupling CD137 activation to PD-1-crosslinking. In CT26 and MC38 syngeneic mouse tumour models, IBI319 restricts T cell co-stimulation to PD-1-rich microenvironments, such as tumours and tumour-draining lymph nodes, hence systemic (liver) toxicity arising from generalised T cell activation is reduced. Besides limiting systemic T cell co-stimulation, the anti-PD-1 arm of IBI319 also exhibits checkpoint blockade functions, with an overall result of T and NK cell infiltration into tumours. Toxicology profiling in non-human primates shows that IBI319 is a well-tolerated molecule with IgG-like pharmacokinetic properties, thus a suitable candidate for further clinical development.

Analysis of Monitoring, Early Warning and Emergency Response System for New Major Infectious Diseases in China and Overseas.

In recent years, the impact of new major infectious diseases on people's normal life is becoming more and more frequent, which has brought great impact on people's life safety and social economy, especially the corona virus disease 2019, which has been sweeping the globe. Public health and disease prevention and control systems in different countries have different performances in response to the pandemic, but they all have exposed many shortcomings. Countries around the world urgently need to improve the monitoring, early warning and emergency response systems for new major infectious diseases. As the outpost and main part of medical rescue, the hospital urgently needs to establish a set of scientifically advanced emergency response mechanism that is suitable for the business process of the medical system and unified standards in order to improve the response efficiency and quality of emergency treatment.

Natural polyphenol assisted delivery of single-strand oligonucleotides by cationic polymers.

Single-strand oligonucleotides provide promising potential as new therapeutics towards various diseases. However, the efficient delivery of oligonucleotide therapeutics is still challenging due to their susceptibility to nuclease degradation and the lack of effective carriers for condensation. In this study, we reported the use of natural polyphenol to facilitate the condensation of single-strand oligonucleotides by cationic polymers. Green tea catechin complexed with single-strand oligonucleotides to form anionic nanoparticles, which were further coated by low molecular weight cationic polymers to increase their cell internalization. The resulting core-shell structured nanoparticles, so-called green nanoparticles (GNPs), showed improved cargo stability, and achieved high efficiency in the delivery of several types of single-strand oligonucleotides including antisense oligonucleotides, anti-miRNA, and DNAzyme. This study provides a facile strategy for the efficient delivery of single-strand oligonucleotides.

Fluorinated Polymer Mediated Transmucosal Peptide Delivery for Intravesical Instillation Therapy of Bladder Cancer.

Surgical intervention combined with intravesical instillation of chemotherapeutics to clear residual cancer cells after operation is the current standard treatment method for bladder cancer. However, the poor bioavailability of active pharmaceutical ingredients for bladder cancer cells on account of the biological barriers of bladder mucosa, together with significant side effects of currently used intravesical medicine, have limited the clinical outcomes of localized adjuvant therapy for bladder cancer. Aiming at improved intravesical instillation therapy of bladder cancer, a fluorinated polyethylenimine (F-PEI) is employed here for the transmucosal delivery of an active venom peptide, polybia-mastoparan I (MPI), which shows selective antiproliferative effect against various bladder cancer cell lines. Upon simple mixing, MPI and F-PET would coassemble to form stable nanoparticles, which show greatly improved cross-membrane and transmucosal penetration capacities compared with MPI alone or nonfluorinated MPI/PEI nanoparticles. MPI/F-PEI shows higher in vivo tumor growth inhibition efficacy for local treatment of a subcutaneous tumor model. More excitingly, as further demonstrated in an orthotopic bladder cancer model, MPI/F-PEI offers remarkably improved therapeutic effects compared to those achieved by free MPI or the first-line bladder cancer drug mitomycin C. This work presents a new transmucosal delivery carrier particularly promising for intravesical instillation therapy of bladder cancer.

Green Tea Catechin Dramatically Promotes RNAi Mediated by Low-Molecular-Weight Polymers.

Cytosolic delivery is the major challenge that limits the clinical translation of siRNA-based therapeutics. Although thousands of polymers have been developed for siRNA delivery, the efficiency-toxicity correlation is unsatisfactory. Here, we report a facile strategy to fabricate core-shell-structured nanoparticles with robust siRNA delivery efficiency. The nanoparticle is prepared by entropy-driven complexation of siRNA with a green tea catechin to yield a negatively charged core, followed by coating low-molecular-weight polymers to form the shell. This supramolecular strategy facilitates the polymers condensing siRNA into uniform nanoparticles. The nanoparticle specifically down-regulates target genes in vitro and in vivo, and efficiently attenuates chronic intestinal inflammation in an inflammatory bowel disease model. Notably, the highly efficient nanoparticles are applicable for various polymers with different topologies and chemical compositions, providing a versatile technique to break down the efficiency-toxicity correlation of cationic polymers. The proposed strategy in this study permits the development of a promising platform for polymer-mediated siRNA delivery.

The fluorination effect of fluoroamphiphiles in cytosolic protein delivery.

Direct delivery of proteins into cells avoids many drawbacks of gene delivery, and thus has emerging applications in biotherapy. However, it remains a challenging task owing to limited charges and relatively large size of proteins. Here, we report an efficient protein delivery system via the co-assembly of fluoroamphiphiles and proteins into nanoparticles. Fluorous substituents on the amphiphiles play essential roles in the formation of uniform nanoparticles, avoiding protein denaturation, efficient endocytosis, and maintaining low cytotoxicity. Structure-activity relationship studies reveal that longer fluorous chain length and higher fluorination degree contribute to more efficient protein delivery, but excess fluorophilicity on the polymer leads to the pre-assembly of fluoroamphiphiles into stable vesicles, and thus failed protein encapsulation and cytosolic delivery. This study highlights the advantage of fluoroamphiphiles over other existing strategies for intracellular protein delivery.

Statistical versus block fluoropolymers in gene delivery.

Fluoropolymers have shown great promise in non-viral gene delivery. The current fluoropolymers developed for gene delivery are synthesized by grafting fluoroalkyls or fluoroaromatics onto cationic polymers. To expand the family of fluoropolymers for the transduction of nucleic acids, new strategies to synthesize fluoropolymers are required. In this study, we synthesized both statistical and block copolymers of poly(2-dimethylaminoethyl methacrylate) (pDMAEMA) and poly(heptafluorobutyl methacrylate) (pHFMA) via reversible addition-fragmentation chain transfer polymerization, and the transfection efficiencies of the fluorocopolymers were evaluated. The statistical fluorocopolymer exhibited dramatically higher performance in gene delivery than the block one, which is attributed to more efficient and sustained DNA uptake by the transfected cells. Moreover, the statistical copolymer of DMAEMA and HFMA showed a fluorine effect in gene delivery, and its efficiency was much superior to non-fluorinated polymers. The results revealed the structure and activity relationships of fluoropolymers consisting of DMAEMA and HFMA, and provided a new insight to guide the design of fluoropolymers for efficient gene delivery.

Screening of efficient siRNA carriers in a library of surface-engineered dendrimers.

Polymers are widely used as non-viral carriers for siRNA delivery, but concern has also arisen in their limited efficacy and inherent toxicity. Whilst many of previous efforts have been documented towards improving the performance of polymers via chemical modifications, the structure-activity relationships (SAR) of these ligand-modified polymers are not well understood. To address this issue, we systemically prepared a library of surface-engineered dendrimers (>300) as the screening pool to discover efficient siRNA carriers. The modified ligands include alkyls and fluoroalkyls, amino acids, benzene derivatives and heterocyclic compounds. Gene silencing results showed that the lead material shows excellent efficacy even in hard-to-transfect cells such as mesenchymal stem cells. The SAR studies revealed that ligands containing appropriate hydrophobicity, or ligands with both hydrophobic and functional atoms/groups are essential for polymers to achive efficient knockdown efficacy. A second-generation library designed based on the above principles further confirms the proposed design criteria. The results enable the future rational design of potent siRNA carriers.

Screening of efficient polymers for siRNA delivery in a library of hydrophobically modified polyethyleneimines.

RNA interference has significant potential as an important tool in biology and medicine. For the development of highly efficient non-viral siRNA carriers, hydrophobic modification on cationic polymers has received increasing attention. Here, we described the screening of efficient siRNA carriers in a library of hydrophobically modified polyethyleneimines (PEIs). Cationic PEI was grafted with hydrophobic ligands including alkanes, cycloalkanes and fluoroalkanes. These modifications significantly improved the gene knockdown efficacy of PEI. Among the functionalized polymers, the fluoroalkylated PEIs showed higher efficacies and lower toxicities than the alkylated and cycloalkylated ones. The top performing polymers in the library efficiently knocked down several target genes in different cell lines without off-target effects. The revealed structure-activity relationships of alkylated, cycloalkylated and fluoroalkylated PEIs in this study provide a new insight into the design of highly efficient and non-toxic siRNA carriers.

Enhanced siRNA delivery of a cyclododecylated dendrimer compared to its linear derivative.

Lipid modification has been widely applied to improve the gene delivery efficacy of cationic polymers. However, this strategy is often associated with relatively low efficacy and high toxicity due to the inherent features of lipids. Here, we describe a novel and facile strategy to develop polymeric gene vectors via cyclododecylation of cationic dendrimers. The synthesized cyclododecylated dendrimer is much more efficient and biocompatible than the dodecylated analogues.