Biology subjects

Zhang, D. K.

Publications and source records attributed to Zhang, D. K..

4 recordsLinked to original sources

bioRxiv2026

Programmable antigen-presenting scaffolds expand rare tumor-antigen-specific T cells from peripheral blood

Adoptive cellular therapies can be effective against solid tumors but rely on the identification and expansion of rare tumor-reactive T cells (TRTs). Here, we utilize antigen-presenting cell-mimetic scaffolds (APC-ms), a modular biomaterial platform that presents defined peptide-HLA and co-stimulatory ligands on a fluid lipid bilayer to selectively recover rare antigen-specific T cells from peripheral blood. Independent variation of peptide-HLA, co-stimulatory ligands, and cytokine support defined a formulation that enriched MART-1-specific T cells to above 2% of CD8+ T cells in 35 of 50 HLA-A*02:01+ healthy donors from low or undetectable baseline frequencies. Compared with mo-DCs, APC-ms achieved greater fold expansion of MART-1-specific T cells with increased functional avidity and preservation of an early differentiation phenotype, and generated a higher number of MART-1-specific clonotypes. In five of eight patients with treatment-naive melanoma, APC-ms could enrich MART-1-specific T cells to a median of 13.7% of CD8+ cells (range 0.30 - 57.2%) Moreover, APC-ms could expand T cells specific for an HLA-A*24:01-restricted personal neoantigen that were previously undetectable in peripheral blood of a patient with melanoma. These findings establish APC-ms as a tunable platform for the recovery of rare TRTs from peripheral blood, supporting its further development for therapeutic TCR discovery and personalized adoptive cell therapy.

immunology↗

bioRxiv2026

AI-enabled discovery of small molecules targeting complementary pathways for hair follicle rejuvenation

Hair thinning arises from multi-faceted dysfunction within the hair follicle, driven by both intrinsic cellular pathways and pathways responding to extrinsic hormonal and microenvironmental cues. Here, we present an AI-enabled discovery framework to discover small molecules that promote hair follicle rejuvenation. This framework integrates graph neural networks trained on phenotypic screening data with structure-based virtual screening to prioritize compounds that modulate complementary biological pathways. Through AI-enabled screening, hit-to-lead optimization, and medicinal chemistry, we identified four compounds that increase follicle dermal papilla cell viability, stabilize hypoxia signaling by inhibiting prolyl hydroxylase domain protein 2 (PHD2), and suppress androgen-mediated follicular miniaturization by inhibiting 5-reductases (5-ARs). RNA sequencing analyses confirmed pathway engagement, and functional validation across primary cells and a 3D hair follicle organoid model demonstrated high activity and cellular specificity. The lead compounds were incorporated into a water-based formulation, where they demonstrated robust solubility and combinatorial efficacy to increase sprouting length of follicle organoids. These results establish an AI-enabled platform for discovering multi-pathway modulators of hair follicle rejuvenation.

bioengineering↗

bioRxiv2025

Development of high-affinity, single-domain protein binders for neutralizing household allergens

Feline, canine, and human dust mite allergens drive significant IgE-mediated allergies in the household environment. Here, we describe the discovery and characterization of novel protein binders, termed AVA, which efficiently bind and disrupt major allergens from cats (Fel d 1), dogs (Can f 1, Can f 2), and dust mites (Der p 1, Der p 2). Leveraging camelid single-domain variable-heavy chain (VHH) antibodies, we identified and optimized VHH sequences with robust affinity towards the individual allergens. AVA disrupted critical allergen substructures (Fel d 1) and catalytic functions (Der p 1) in molecular dynamics simulations and in in vitro assays, respectively. Paired with robust thermostability and non-toxic in vitro viability profiles, AVA represents a promising approach for downstream household allergen mitigation.

bioengineering↗

bioRxiv2022

SlideCNA: Spatial copy number alteration detection from Slide-seq-like spatial transcriptomics data

Solid tumors are spatially heterogeneous in their genetic, molecular and cellular composition, and this variation can be meaningful for diagnosis, prognosis and therapy. Recent spatial profiling studies have mostly charted genetic and RNA variation in tumors separately. To leverage the potential of RNA to identify copy number alterations (CNAs), we developed SlideCNA, a computational tool to extract sparse spatial CNA signals from spatial transcriptomics data, using expression-aware spatial binning. We test SlideCNA on simulated and real Slide-seq data of metastatic breast cancer (MBC) and demonstrate its potential for spatial sub-clone detection.

bioinformatics↗