Yang Liu

Intracellular nucleotide imbalance between ribonucleotides and deoxyribonucleotides can trigger cytosolic mitochondrial DNA (mtDNA) release and subsequent activation of the cGAS–STING pathway. However, fluoropyrimidine‐induced nucleotide imbalance is constrained by their metabolic instability. Here, we leverage ribonucleotides to amplify floxuridine (FUDR)‐induced mtDNA release and cGAS–STING activation for enhanced cancer chemoimmunotherapy. We identified that cytidine monophosphate (CMP) significantly enhances FUDR‐mediated activation of the mtDNA‐driven cGAS–STING pathway, inducing over 300‐fold upregulation of the interferon gene Ifnb1 and initiating STING‐dependent antitumor immunity. Genome‐wide CRISPR‐Cas9 screening identified five pyrimidine‐metabolizing enzymes (CMPK1, CMPK2, TYMP, UPP1, and UPP2) that are responsible for the metabolic instability of floxuridine monophosphate (FdUMP). CMP and its intracellular metabolites can metabolically block these enzymes, thereby increasing the peak intracellular concentration of FdUMP by over 500‐fold and extending its half‐life by more than 20‐fold, which in turn promotes sustained intracellular nucleotide imbalance. To translate this mechanism into therapy, we co‐encapsulated FdUMP and CMP into hybrid lipid nanoparticles (FC‐NPs). FC‐NPs robustly activated STING‐dependent antitumor immunity, achieving remarkable therapeutic efficacy in multiple murine colorectal cancer (CRC) models. Our study not only addresses the long‐standing issue of fluoropyrimidine metabolic instability but also reveals a novel ribonucleotide‐mediated immunomodulatory mechanism, providing a promising strategy to potentiate chemoimmunotherapy in CRC.

An ideal radioimmunotherapy eradicates primary tumors and drives immune clearance of residual or metastatic tumor cells, but its clinical translation is severely limited by systemic immune toxicity and the immunosuppressive tumor microenvironment (TME). Here, we constructed engineered Escherichia coli Nissle 1917 with a tannic acid‐mediated boronophenylalanine coating and a radiation‐responsive genetic circuit, enabling TME‐responsive boron delivery for boron neutron capture therapy (BNCT). BNCT‐mediated selective tumor killing spared intratumoral probiotics, whose integrated genetic circuit was triggered by the low‐level incidental radiation generated during the BNCT process, including γ‐rays, to drive CXCL10 production, forming a feedback loop to remodel the TME. This strategy achieved robust tumor eradication, inhibited distal tumor growth and post‐surgical metastasis in murine models, pioneering a BNCT‐based radioimmunotherapy modality.

Boron neutron capture therapy (BNCT) is an emerging targeted radiotherapy technology that enables precise eradication of tumor cells. The development of efficient boron carriers is crucial for the advancement of BNCT technology. Notably, biomolecular carriers currently represent the only class of drug carriers that has achieved market approval (e.g., boronophenylalanine [BPA] in Japan), underscoring their pivotal role in clinical applications. Their outstanding biocompatibility, high payload capacity, and tumor‐targeting capabilities align closely with the stringent requirements of BNCT drug delivery. For instance, amino acid‐based carriers (such as BPA) utilize L‐type amino acid transporter 1 (LAT1) for tumor‐specific accumulation; nucleoside prodrugs are activated by thymidine kinase 1 (TK1) and incorporated into tumor DNA; carbohydrate‐based carriers improve solubility and targeting through glucose transporters (GLUTs); peptide carriers facilitate cellular uptake via receptor‐mediated endocytosis or cell‐penetrating peptides; and liposomes leverage the enhanced permeability and retention (EPR) effect together with active‐targeting modifications for enhanced tumor delivery. Nevertheless, delivering ultrahigh doses of boron remains a major challenge. Biomacromolecules, particularly albumin‐based systems, have garnered increasing attention because of their excellent biosafety and high boron‐loading potential, offering promising avenues for overcoming dose delivery barriers in BNCT. This review systematically summarizes the recent advances in biomolecular carriers for BNCT and highlights emerging applications of protein‐based boron carriers, addressing a notable gap in the comprehensive review of biomolecular strategies within the BNCT drug delivery field.

The targeted transport of nanomedicines is often impeded by various biological events in the body. Viruses can hijack host cells and utilize intracellular transcription and translation biological events to achieve their replication. Inspired by this, a strategy to hijack endogenous products of biological events to assemble into intracellular functional nanoparticles is established. It has been shown that, following tumor vessel destruction therapy, injected cell permeable small molecule drugs bisphosphonate can hijack the hemorrhagic product iron and self‐assemble into peroxidase‐like nanoparticles within tumor‐infiltrating macrophages. Unlike free drugs, the generated intercellular nanoparticles can specifically stress mitochondria, resulting in immune activation of macrophages in vitro and polarizing tumor‐associated macrophages (TAMs) from immunosuppressive to tumoricidal and increasing the recruitment of T cells deep within tumor. The hijacking self‐assembly strategy significantly inhibits tumor growth compared with the treatment of vascular‐disrupting agents alone. Using bisphosphonate to hijack the metabolite associated with hemorrhage, iron, to fabricate functional nanoparticles within specific cells, which may open up new nanotechnology for drug delivery and small molecular drug development.

Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans, secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo[1,5-a]pyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log₁₀ CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU.

Tuberculosis (TB) is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in Mycobacterium tuberculosis. Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) and total drug-resistant tuberculosis (TDR-TB), due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of M. tuberculosis for the development of new therapeutics to meet the immense challenge of global health.

Mycobacterium abscessus (MAB), which manifests in the pulmonary system, is one of the neglected causes of nontuberculous mycobacteria (NTM) infection. Treatment against MAB is difficult, characterized by its intrinsic antibiotic drug resistance. Lysine acetylation can alter the physiochemical property of proteins in living organisms. This study aimed to determine if this protein post-translational modification (PTM) exists in a clinical isolate M. abscessus GZ002. We used the antiacetyl-lysine immunoprecipitation to enrich the low-abundant PTM proteins, followed by the LC–MS/MS analysis. The lysine acetylome of M. abscessus GZ002 was determined. There were 459 lysine acetylation sites found in 289 acetylated proteins. Lysine acetylation occurred in 5.87% of the M. abscessus GZ002 proteome, and at least 25% of them were growth essential. Aerobic respiration and carbohydrate metabolic pathways of M. abscessus GZ002 were enriched with lysine acetylation. Through bioinformatics analysis, we identified four major acetyl motif logos (K^acY, K^acF, K^acH, and DK^ac). Further comparison of the reported M. tuberculosis (MTB) acetylomes and that of MAB GZ002 revealed several common features between these two species. The lysine residues of several antibiotic-resistance, virulence, and persistence-related proteins were acetylated in both MAB GZ002 and MTB. There were 51 identical acetylation sites in 37 proteins found in common between MAB GZ002 and MTB. Overall, we demonstrate a profile of lysine acetylation in MAB GZ002 proteome that shares similarities with MTB. Interventions that target at these conserved sections may be valuable as anti-NTM or anti-TB therapies.