Wing-Tak Wong

Illicit use of messenger ribonucleic acid (mRNA) agents represents an imminent threat to gene doping control in equine sports. The effectiveness and safety of lipid nanoparticle‐encapsulated mRNA agents (LNP‐mRNA), which have been well‐proven during COVID‐19 pandemic, have resulted in prominent growth of the interest on LNP‐mRNA agents for expressing desired proteins in vivo. The vast number of potential performance‐enhancing mRNAs has demanded cost‐effective and reliable methods for their detections. This study employed a multimodal analysis approach to detect an LNP‐mRNA product (“LNP‐ epo ” hereafter) arising from encapsulation of a black‐market product of human erythropoietin (hEPO) mRNA. Lipid nanoparticle (LNP) components were detected by liquid chromatography/high‐resolution tandem mass spectrometry after supported liquid extraction; hEPO mRNA was detected by reverse transcription quantitative polymerase chain reaction after RNA extraction; hEPO protein was detected by sandwich enzyme‐linked immunosorbent assay. Comparative elimination analysis of LNP‐ epo in blood samples collected from an administered horse showed the longest detection time achieved by LNP monitoring (at least 34‐day postadministration), followed by hEPO mRNA detection (up to 30 days in whole blood; up to 17 days in plasma), and shortest by hEPO protein detection (up to 3 days). Together with its low analysis cost, broad coverage of LNP components, expandable scope and independence from mRNA sequence modifications and the need for specific reagents (e.g., primers, antibodies), the detection of LNP can be a fit‐for‐purpose screening method for monitoring the misuse of LNP‐mRNA in equine sports. The other two approaches could provide insight on the intentional effect elicited by LNP‐mRNA.

Bispecific antibodies (BsAbs) represent a growing class of cancer immunotherapeutics, yet their wider adoption remains limited by complex recombinant production and limited manufacturing efficiency. Here, we report a chemically assembled macrophage‐engaging glypican‐3 × signal regulatory protein‐α (SIRP‐α) bispecific antibody for the treatment of liver cancer. Using our bifunctional linker, glypican‐3‐binding peptide dimers were conjugated to a native anti‐SIRP‐α IgG via a rapid one‐pot, two‐step process, yielding a novel dendritic bispecific antibody (dBsAb). Such a construct simultaneously targets glypican‐3‐positive hepatocellular carcinoma cells and blocks the CD47–SIRP‐α axis, thereby promoting macrophage engagement and phagocytosis. In vitro studies showed substantially enhanced macrophage adhesion and tumor cell clearance compared with the monoclonal antibody. In an in vivo experiment, dBsAb demonstrated a 68% reduction in tumor growth, with increased macrophage infiltration, M1 polarization, and elevated antigen presentation without observable systemic toxicity. This chemical assembly approach offers a practical alternative to recombinant methods for constructing bispecific antibodies and may facilitate the development of macrophage‐directed immunotherapies.

The complex immunosuppressive microenvironment of triple‐negative breast cancer (TNBC) remains a major obstacle in attaining long‐term clinical success and halting metastatic progression. To address this, the rational design of tumor microenvironment (TME)‐responsive nanotheranostics is crucial for converting ‘cold’ tumors into ‘hot’ ones through synchronized imaging and precision therapy. Herein, we present a biomimetic, stimuli‐activatable assembly (Au/Ag@HMON‐NLG@CCM) utilizing a H ₂ O ₂ ‐responsive Au/Ag core to facilitate NIR‐II ratiometric photoacoustic (PA) detection and thermal ablation. By encapsulating the IDO inhibitor NLG919 within a hollow mesoporous organosilica (HMON) shell and coating with cancer cell membrane (CCM), the system achieves superior tumor‐targeting and synergistic immuno‐photothermal effects. Specifically, TME‐overexpressed H ₂ O ₂ ‐induces the oxidative degradation of the Ag, shifting the absorption into the NIR‐II window to enable robust ratiometric PA visualization and efficient PTT (η = 42.8%). The resulting hyperthermia triggers immunogenic cell death (ICD) to initiate antigen release, while NLG919‐mediated IDO1 blockade alleviates local immunosuppression, collectively remodeling the ‘cold’ TME. In bilateral tumor models, this integrated strategy effectively suppresses both primary lesions and distant metastases, demonstrating a potent systemic abscopal effect and durable antitumor immunity. Overall, this multifunctional nanoplatform provides a transformative strategy for NIR‐II‐guided precision medicine, offering a robust approach to eradicating metastatic and immunosuppressive malignancies.

Current therapies for Parkinson's disease (PD) fail to concurrently address α ‐synuclein ( α ‐syn) aggregation and microglia‐mediated neuroinflammation. Herein, we engineer a near‐infrared‐II (NIR‐II) phototheranostic nanoplatform, CAG/FD1080@MM‐aTRPV4, for synergistic regulation of microglial function and real‐time monitoring of PD pathology. We first encapsulated cycloastragenol (CAG), a bioactive compound derived from Astragalus , into liposomes. These liposomes were then fused with biomimetic microglial membrane‐loaded FD1080 photothermal imaging agent, followed by modification with a transient receptor potential vanilloid 4 (TRPV4)‐targeting antibody. In vitro studies using α ‐syn‐treated cultured microglia and in vivo studies in an α ‐syn‐overexpressing mouse model collectively demonstrate the efficacy of our strategy. It not only enables precise microglial delivery of CAG to reprogram metabolism but also sustains lysosomal function via photothermal activation of the TRPV4/CaMKK β /AMPK/mTOR pathway, ultimately enhancing phagocytosis. Importantly, the encapsulated FD1080 (for microglial tracking) and an anti‐ α ‐syn‐conjugated indocyanine green (anti‐ α ‐syn‐ICG) probe enable dual‐modality NIR‐II photoacoustic‐fluorescence imaging, allowing real‐time visualization of both microglial dynamics and α ‐syn clearance. This work pioneers a photothermal immunomodulation strategy using a Chinese herb‐derived compound, presenting a versatile theranostic platform and novel mechanistic insights for microglia‐targeted PD therapy.

Postoperative lung recurrent cancer exhibited characteristics of an immunosuppressive tumor microenvironment (TME) and low immunogenicity, hindering the therapeutic efficacy of monotherapy, which requires a combination of several treatment modules. Strategies that activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and repolarize tumor-associated macrophages (TAMs) toward the antitumoral M1-like phenotype to reverse the TME are rarely reported. The triggering receptor expressed on myeloid cells 2 (TREM2) is a promising therapeutic target, owing to its critical role in enhancing tumor immunogenicity within the TME. This work describes the design of an anti-TREM2-modified FePt-based biomimetic nanovesicle (FP/Vad@CC-aT2) for the delivery of STING agonist Vadimezan (Vad), which increases tumor immunogenicity to sensitize recurrent lung tumors to immunotherapy. FePt not only acted as a photoacoustic/magnetic resonance imaging contrast agent but also enhanced ferroptosis by catalyzing a Fenton reaction with reactive oxygen species production under X-rays. Simultaneously, anti-TREM2 effectively repolarized TAMs into M1-type macrophages, thereby reversing immunosuppressive TME together with a Vad-activated STING pathway, which promoted the maturation of dendritic cells and enhanced the infiltration of cytotoxic T lymphocytes. Therefore, this study highlighted the FP/Vad@CC-aT2-mediated cascade immune response for suppressing lung cancer recurrence that involves ferroptosis potentiation, TAM repolarization, and STING pathway activation.

Ranitidine is a histamine H ₂ ‐receptor antagonist commonly used to treat gastric ulceration in horses. The author's laboratory conducted a study some years ago in the early 2000s on its metabolism as well as its urinary elimination profile in two geldings. With the technology advancement as well as popularity of blood for doping control testing, the laboratory has recently conducted another administration trials of the substance in six horses to study the in vivo metabolism of ranitidine, aiming to identify and reinvestigate the appropriate target(s) for controlling misuse of ranitidine in horses as well as to study its elimination in blood. To study the elimination and biotransformation of ranitidine, administration experiments were performed by giving six castrated horses (geldings) each 25 mL of Ulcerguard oral paste (equivalent to 9.8 g of ranitidine) in the morning and 20 mL of oral paste (equivalent to 7.9 g of ranitidine) in the afternoon daily for eight consecutive days. The postulated in vivo metabolites included ranitidine‐S‐oxide (M1), ranitidine‐N‐oxide (M2), desmethylranitidine (M3a/b) and furoic acid analogue of ranitidine (M4), resulting from oxidation, demethylation and oxidative deamination of ranitidine. To control the misuse of ranitidine in horses, elimination profiles of urinary and plasma ranitidine were established. Free ranitidine was detectable for at most 8 days and 72 h in urine and plasma, respectively. Both metabolites ranitidine‐S‐oxide and ranitidine‐N‐oxide were detected for 8 days, and therefore, they could be monitored alongside the parent drug as evidence that the substance has gone through the horse's body.

Chemoresistance and metastasis are the main obstacles to the clinical success of anticancer treatment and are responsible for most cancer deaths. Developing effective approaches to reverse chemoresistance and inhibit metastasis is essential for efficient chemotherapy. Mitochondria are important sources of cellular energy and are involved in mediating chemoresistance and driving tumor metastasis. Due to the relatively weak DNA repair capacity of mitochondria, targeting mitochondria may reverse chemoresistance and provide a paradigm for metastatic cancer treatment. Herein, exosomes (Exos) modified with integrin ligands and mitochondriotropic molecules are synthesized for encapsulating oxaliplatin (OXA) to construct a sequentially targeted and mitochondrion‐dysfunctional nanodrug (OXA@Exo‐RD). Subsequent investigations confirm that OXA@Exo‐RD targeted cancer cells and mitochondria in sequence, and OXA delivered to mitochondria lacking DNA repair mechanisms reduce the likelihood of deactivation. Furthermore, the OXA@Exo‐RD promotes the overproduction of ROS, inhibited ATP generation, and induces mitochondria‐mediated apoptosis and mitochondrial dysregulation. Finally, OXA@Exo‐RD shows the potential to inhibit the growth and metastasis of HCT116/OXA cells in vitro, which is further validated in subcutaneous and orthotopic CRC models, as well as in CRC metastasis models. Taken together, this dual‐targeting nanomedicine induces apoptosis via mitochondrial signaling pathways, providing an attractive strategy for the treatment of drug‐resistant CRC.

We present a water-soluble fluorescence/MR dual-modality probe NBD[Gd] for H₂S detection.

A novel peptidic bispecific antibody (pBsAb) is developed by integrating EGFR-binding cyclic peptide with an anti-SIRP-α antibody, promotes cancer cells recognition, suppresses "don't eat me" signal, and enhances phagocytosis and tumour infiltration.