Jingya Qin

The broader clinical use of bispecific T cell engagers for inducing anti-tumour toxicity is hindered by their on-target off-tumour toxicity and the associated neurotoxicity and cytokine-release syndrome. Here we show that the off-tumour toxicity of a supramolecular bispecific T cell engager binding to the T cell co-receptor CD3 and to the human epidermal growth factor receptor 2 on breast tumour cells can be halted by disengaging the T cells from the tumour cells via the infusion of the small-molecule drug amantadine, which disassembles the supramolecular aggregate. In mice bearing human epidermal growth factor receptor 2-expressing tumours and with a human immune system, high intravenous doses of such a ‘switchable T cell nanoengager’ elicited strong tumour-specific adaptive immune responses that prevented tumour relapse, while the infusion of amantadine restricted off-tumour toxicity, cytokine-release …

Delivery of nucleic acids, such as mRNA, to immune cells has become a major focus in the past decade with ionizable lipid nanoparticles (LNPs) emerging as a clinically-validated delivery platform. LNPs—typically composed of ionizable lipids, cholesterol, phospholipids, and polyethylene glycol lipids —have been designed and optimized for a variety of applications including cancer therapies, vaccines, and gene editing. However, LNPs have only recently been investigated for delivery to T cells, which has various therapeutic applications including the engineering of T cell immunotherapies. While several LNP formulations have been evaluated for mRNA delivery, recent work has demonstrated that the utilization of cholesterol analogs may enhance mRNA delivery. Other studies have shown that cholesterols modified with hydroxyl groups can alter endocytic recycling mechanisms. Here, we engineered a library of …

The development of lipid nanoparticle (LNP) formulations for targeting the bone microenvironment holds significant potential for nucleic acid therapeutic applications including bone regeneration, cancer, and hematopoietic stem cell therapies. However, therapeutic delivery to bone remains a significant challenge due to several biological barriers, such as low blood flow in bone, blood–bone marrow barriers, and low affinity between drugs and bone minerals, which leads to unfavorable therapeutic dosages in the bone microenvironment. Here, we construct a series of bisphosphonate (BP) lipid-like materials possessing a high affinity for bone minerals, as a means to overcome biological barriers to deliver mRNA therapeutics efficiently to the bone microenvironment in vivo. Following in vitro screening of BP lipid-like materials formulated into LNPs, we identified a lead BP-LNP formulation, 490BP-C14, with enhanced …

mRNA therapeutics are promising platforms for protein replacement therapies and gene editing technologies. When delivered via non-viral gene delivery systems, such as lipid nanoparticles (LNPs), mRNA therapeutics are easy to produce and show low toxicity and immunogenicity. However, LNPs show limited delivery efficiency and tissue specificity in certain applications. To overcome this, we designed RGD peptide (Arg-Gly-Asp) based ionizable lipids, which can be formulated into LNPs for integrin binding on cells and targeted mRNA delivery. RGD-LNPs were formulated using microfluidic devices and screened in vitro for size, mRNA encapsulation efficiency, transfection efficiency, and cell viability. A lead candidate, 1A RGD-based hybrid LNP, showed effective mRNA encapsulation and transfection, and was selected for further testing, including the co-delivery of Cas9 mRNA and sgRNA for gene editing …

Elastin-like polypeptides (ELPs) are thermoresponsive biopolymers that undergo an LCST-like phase transition in aqueous solutions. The temperature of this LCST-like transition, Tt, can be tuned by varying the number of repeat units in the ELP, sequence and composition of the repeat units, the solution conditions, and via conjugation to other biomacromolecules. The self-assembly of nanostructures from elastin-like (poly) peptide (ELP) containing block copolymers has been a subject of intense investigation over decades. However, short synthetic ELPs have rarely been used due to their high inverse transition temperature; the use of short ELPs has largely been limited to polymer conjugates. We have sought ways to use these short ELPs in designing versatile, temperature-responsive assemblies.

The self-assembly of nanostructures from conjugates of elastin-like peptides and collagen-like peptides (ELP-CLP) has been studied as means to produce thermoresponsive, collagen-binding drug delivery vehicles. Motivated by our previous work in which ELP-CLP conjugates successfully self-assembled into vesicles and platelet-like nanostructures, here, we extend our library of ELP-CLP bioconjugates to a series of tryptophan/phenylalanine-containing ELPs and GPO-based CLPs [W2Fx-b-(GPO)y] with various domain lengths to determine the impact of these modifications on the thermoresponsiveness and morphology. The lower transition temperature of the conjugates with longer ELP or CLP domains enables the formation of well-defined nanoparticles near physiological temperature. Moreover, the morphological transition from vesicles to platelet-like nanostructures occurred when the ratio of the lengths of …