Nanoparticulate drug delivery systems (NDDS) have revolutionized modern medicine by significantly improving drug targeting, bioavailability, and therapeutic efficacy. Despite the clinical success of over 90 approved nanomedicines, the development of NDDS remains challenging due to the complexity of formulation design, optimization, and characterization processes. Artificial intelligence, particularly machine learning (ML), offers powerful data analytics and predictive capabilities that can address these challenges. This review systematically summarizes recent advances in ML applications across various NDDS formulations, including polymeric nanoparticles, lipid nanoparticles, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, nanosuspensions, lipid-based hybrid NDDS, self-emulsifying drug delivery systems, niosomes, and nanocrystals. We also summarize how ML algorithms could help predict critical quality attributes of NDDS, such as particle size, shape, surface properties, drug encapsulation efficiency, drug loading efficiency, drug release behavior, and stability. Furthermore, we discuss existing challenges and prospects for the formulation development empowered by ML in NDDS. In conclusion, this review provides a comprehensive overview of the transformative potential of ML in improving the formulation development of nanomedicines, ultimately accelerating their clinical translation.

Artificial intelligence (AI) is a transformative technique for drug development, and it has been widely applied in pharmaceutical industry and academia. Pulmonary drug delivery systems (PDDS) are preferred for treating respiratory diseases due to their ability to provide localized and rapid action with fewer side effects. The integration of AI and Machine Learning (ML) has significantly accelerated the development of PDDS by enhancing both respiratory disease detection, and different stages during PDDS development. This paper provides an overview of the present landscape by literature analysis of the key areas of research. This review first introduces the fundamental principles of AI/ML and how they are applied in respiratory disease detection and diagnostics, highlighting FDA-approved software used in this field. Furthermore, we examine the role of AI in different stages during the development of PDDS, from identifying novel drug candidates to optimizing formulations and drug delivery mechanisms. The review also discusses regulatory and ethical considerations, along with existing challenges during AI-driven PDDS development. By addressing these key aspects, we provide insights into the revolutionary potential of AI/ML in advancing pulmonary drug delivery and improving therapeutic outcomes.

Lipid nanoparticles (LNPs) hold significant potential for mRNA-based therapeutics, as evidenced by their successful use in SARS-CoV-2 mRNA vaccines. LNPs effectively protect and transport mRNA to target sites, thereby ensuring its stability and efficient transfection. Despite the progress, some challenges remain in the development of mRNA-LNP delivery systems, such as limited targeting specificity, the complexity of formulations, and the time-consuming and high-throughput screening process. Artificial intelligence (AI) has emerged as a powerful tool to address these challenges, accelerating the design and optimization process of LNPs. AI-guided approaches can improve the efficiency of lipid structure and formulation screening by rapidly identifying key design parameters and employing predictive modeling to optimize LNP properties. The combination of AI and LNP technology offers significant advantages, including enabling the design of more personalized and precise delivery systems, streamlining the development process, and reducing the cost. This review discusses recent advancements in AI-guided mRNA-LNP delivery systems and highlights their potential to revolutionize mRNA therapeutics.

The rapid evolution of influenza viruses, driven by high mutation rates and cross-species transmission, underscores the importance of discovering antivirals with novel mechanisms of action and distinct resistance profiles. The influenza virus RNA polymerase, a highly conserved heterotrimeric complex, comprises polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA) in influenza A and B viruses, or polymerase 3 protein (P3) in influenza C and D viruses. This complex is essential for viral genome replication and transcription, rendering it a critical target for antiviral intervention. Over the past two decades, research on influenza polymerase (FluPol) has advanced from fundamental studies to drug development and clinical application. By 2025, six FluPol-targeting drugs have received regulatory approval: the PA inhibitors baloxavir marboxil, suraxavir marboxil, seloxavir marboxil, and pixavir marboxil; the PB1 inhibitor favipiravir; and the PB2 inhibitor onradivir, with several additional candidates progressing to clinical research. This review summarizes the structure and function of influenza polymerase and the mechanisms of action of different inhibitors, highlighting the discovery and clinical effectiveness of the newly approved FluPol-targeting drugs. It addresses the potential of FluPol inhibitors against highly pathogenic avian influenza and the challenges posed by resistance mutations.

Protein kinases, as one of the most important human enzymes, are signaling molecules that regulate almost all cell activities, including growth, cell division and metabolism. Dysfunction of these cellular pathways can lead to a variety of human diseases. Accumulating evidence on the down-regulation of key protein kinases in diseases has made a big progress. The down-regulation is related to cancer, heart disease, neurodegenerative diseases and other diseases. Thus, in this review, we defined the classifications of protein kinases and demonstrated the mechanisms of protein kinase activators in the treatment of human diseases, summarized the research progress of protein kinase activators, and further discussed the development progress of protein kinase activators in clinical stage. Accordingly, activation of protein kinases has become a crucial target for drug development. With the in-depth understanding of protein kinase functions and regulation mechanisms, the development of new protein kinase activators may continue to be a rapidly growing field, which will help to develop more accurate and effective targeted therapeutic strategies in the near future.

Deubiquitinase-targeting chimeras (DUBTAC), as a highly promising emerging technology, can precisely remove ubiquitin chains from target proteins by recruiting deubiquitinases (DUBs), thereby enhancing the stability of the target proteins. Multiple functional proteins, such as the tumor suppressor proteins p53, RB, PTEN, upon stabilization by DUBTAC, can effectively restore or enhance their physiological functions, thus achieving therapeutic effects. Currently, the DUBTAC technology is still in its early stage of development, yet it has broad application prospects and represents a technological approach for developing various “undruggable” targets. This article delves into the design strategy of DUBTAC, and screens and recommends some candidate proteins with the potential to serve as drug targets. We aim to provide perspective in drug design, structural optimization, target selection, and related aspects.

Artificial intelligence (AI) has revolutionized the design of antibodies and RNA aptamers, driving significant advancements in molecular therapeutics. In antibody design, AI enables accurate structure prediction and optimization of binding affinity, specificity, and stability, thereby accelerating the development of therapies targeting challenging antigens, such as those associated with viral infections and cancer. By integrating sequence and structural data, AI significantly reduces experimental costs and development timelines, streamlining the creation of next-generation antibody-based therapeutics. Similarly, AI has transformed RNA aptamer design, addressing long-standing challenges in structure prediction and binding optimization. AI-driven approaches allow for the rapid generation of aptamers with enhanced specificity, stability, and functional properties, expanding their potential applications in both therapeutics and diagnostics. These advancements offer scalable, cost-effective, and highly customizable solutions for precision medicine. As AI systems continue to evolve and integrate with experimental validation, they hold immense promise for developing more effective treatments for complex diseases, including cancer, autoimmune disorders, and viral infections. This marks the beginning of a new era in therapeutic innovation, where AI plays a pivotal role in addressing the challenges of modern medicine.

The susceptibility to ferroptosis partially determines the efficacy of tyrosine kinase inhibitors (TKIs) in hepatocellular carcinoma (HCC), exposing a mechanistic vulnerability that can be therapeutically exploited. The development of deuterated compounds is a promising strategy for the improvement of anti-tumor efficacy. Here, we identified HCC with higher level of ferroptosis-resistance exhibited insensitive to TKIs, which could be reversed by deuterated TKIs. Aldehyde oxidase 1 (AOX1) was screened as a critical gene mediating the responsiveness to deuterated TKIs-induced ferroptosis in HCC. The presence of a pyridyl tri-deuterated methanamide contributed to the upregulation of AOX1 in a structure-dependent manner, thereby promoting ferroptosis. Mechanistically, AOX1 inhibited sirtuin 6-mediated deacetylation of H3K9 and H3K56, leading to transcriptional activation of acyl-CoA synthetase long chain family member 5, which resulted in poly-unsaturated fatty acids hyperaccumulation-induced ferroptosis. Additionally, HCC with lower AOX1 expression conferred better efficacy to deuterated TKIs. In patient cohorts with HCC, those with lower AOX1 expression exhibited a more pronounced therapeutic response to deuterated sorafenib. Overall, the present study elucidates the mechanism by which deuterated TKIs reverse TKI resistance by promoting ferroptosis and suggests that AOX1 could serve as a biomarker to guide clinical decision-making for deuterated TKI treatment in HCC.

Parkinson's disease (PD) is a severe neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. Emerging evidence suggests that deubiquitinating enzymes (DUBs), which regulate protein homeostasis through the cleavage of ubiquitin chains, play critical roles in PD pathogenesis. In this study, we discovered that a DUB, ovarian tumor deubiquitinase 6A (OTUD6A), was significantly upregulated in both PD patients and PD mouse models. Notably, OTUD6A deficiency effectively protected dopaminergic neurons from degeneration and improved motor deficits in both acute and chronic PD mouse models. Through comprehensive mass spectrometry analysis and co-immunoprecipitation assays, we identified that actin gamma 1 (ACTG1) serves as a key substrate of OTUD6A. Mechanistically, OTUD6A specifically interacts with the 8–181 aa domain of ACTG1 and preferentially cleaves K48-linked polyubiquitin chains, thereby enhancing ACTG1 protein stability in neuronal cells. The stabilized ACTG1 subsequently binds to p53 and facilitates its nuclear translocation, leading to the transcriptional activation of pro-apoptotic genes and promoting neuronal apoptosis. Collectively, our findings demonstrate that OTUD6A promotes dopaminergic neuron degeneration and PD progression by deubiquitinating and stabilizing ACTG1, which in turn activates a p53-dependent apoptotic pathway. These findings identify OTUD6A as a potential therapeutic target for PD intervention.

Obesity-prone (OP) individuals exhibit an intrinsic predisposition to obesity and associated metabolic disorders, and early intervention in this population holds significant clinical value; however, the underlying mechanisms driving this susceptibility remain largely obscure. This study enrolled 46 OP subjects without diagnosed metabolic diseases and 35 healthy controls. Our findings revealed that, despite not reaching obesity diagnoses, OP subjects exhibited significant metabolic disturbances strongly associated with gut microbiota dysbiosis. They also displayed disturbed bile acid (BA) profiles, with depleted glycodeoxycholic acid (GDCA) identified as the most potent discriminator between the OP and healthy controls. Fecal microbiota transplantation (FMT) recapitulated metabolic dysfunction and BA pool remodeling, mediated by dysregulated hepatic expression of BA synthesis genes of Cyp8a1, Cyp7a1, and Cyp7b1. Notably, FMT-OP mice also phenocopied the diminished GDCA levels observed in OP subjects. GDCA supplementation in obese mice markedly improved body weight, hepatic steatosis, and metabolic dysfunction. Mechanistically, GDCA exerted anti-obesity effects by activating the TGR5 signaling, which enhanced brown adipose tissue (BAT) thermogenesis and stimulated ileal glucagon-like peptide-1 (GLP-1) secretion, thereby ameliorating obesity and associated metabolic dysregulation. Thus, these findings indicate that gut microbiota-driven dysregulation of BA signaling, particularly impaired TGR5 activation due to diminished GDCA, underlies glycolipid metabolic dysfunction in OP individuals.

Oxaliplatin, a chemotherapeutic agent commonly used in colorectal cancer treatment, frequently induces chemotherapy-induced peripheral neuropathy (CIPN), with mechanical allodynia as a dose-limiting neurological complication. However, the precise pathophysiological mechanism underlying this sensory dysfunction remains inadequately elucidated. This study identifies Kv4.3 channel dysfunction in C-low threshold mechanoreceptors (C-LTMRs), a subset of tyrosine hydroxylase–positive (TH⁺) sensory neurons in the dorsal root ganglia (DRG), as the critical driver of oxaliplatin-induced mechanical allodynia. Using electrophysiological, pharmacological, and genetic approaches in mouse models, we have demonstrated that oxaliplatin selectively alters the firing pattern of C-LTMRs and enhances their excitability, particularly in response to low-intensity stimuli. This effect is mediated by Kv4.3 channel dysfunction within C-LTMRs, which underlies the pathological conversion of innocuous touch to pain. Critically, pharmacological inhibition or neuron-specific knockdown of Kv4.3 channels exacerbated mechanical allodynia, while Kv4.3 channel activation reversed neuronal hyperexcitability and alleviated oxaliplatin-induced mechanical allodynia. Thus, Kv4.3 dysfunction constitutes a core pathogenic mechanism of oxaliplatin-induced mechanical allodynia. Targeted enhancement of the Kv4.3 channel activity in C-LTMRs represents a promising precision analgesic strategy for this condition.

Clostridium perfringens alpha toxin (CPA), a zinc-dependent phospholipase C, is a key virulence factor in gas gangrene. While its membrane-disrupting cytotoxicity is well characterized, its capacity to modulate neutrophil function and promote pathological inflammation is poorly defined. Here, we show that CPA induces neutrophil extracellular trap (NETs) formation by mobilizing and functionally reprogramming immature neutrophils. In a murine model, CPA challenge caused dose-dependent mortality and multi-organ injury, driven by a dramatic expansion of a pro-NETotic immature neutrophil subset identified by single-cell RNA sequencing. This was confirmed by elevated systemic NETs markers and extensive NETs deposition in damaged tissues. Mechanistically, CPA directly triggered reactive oxygen species (ROS)-dependent, peptidylarginine deiminase 4 (PAD4)-mediated NETosis in both murine and human neutrophils, revealing a conserved pathogenic mechanism. Importantly, therapeutic targeting of the NETotic pathway—via PAD4 inhibition, (Deoxyribonuclease I) DNase I treatment, or neutrophil depletion—significantly reduced tissue damage and improved survival. These findings identify a CPA–neutrophil–NETs axis as a central driver of immunopathology. Our study reframes CPA from a classical cytolysin to a potent immunomodulatory toxin that hijacks neutrophil fate. Our findings validate the NETotic pathway as a critical therapeutic target, providing a strong rationale for developing host-directed therapies—potentially in combination with toxin-neutralizing agents—to combat severe toxin-driven diseases.

COVID-19 and its variants have spread around the world, triggering a range of long-term sequelae and leading to the need for broadly effective vaccines. We have established a new fusion protein combining the receptor-binding domain region (SF2) and a newly identified conserved binding region (SF5) from the spike of SARS-CoV-2. This fusion protein (COVID19-SF2+SF5) specifically bound to VERO-E6 cells with higher efficiency than either region alone. Antibodies raised in mice against COVID19-SF2+SF5 cross-reacted with every fragment of SARS-CoV-2 and SARS. Additionally, antibodies against the fusion protein effectively neutralize pseudoviruses of both wild-type and mutant strains of SARS-CoV-2 (including BA.3, XBB.1.5, and EG.5), as well as SARS pseudoviruses. Protein interaction prediction and binding affinity determination revealed that the fusion protein exhibits strong binding capacity to three key host molecules: heparan sulfate proteoglycan (HSPG), neuropilin-1 (NRP1), and cluster of differentiation 147 (CD147). Analysis of representative viruses from four coronavirus genera (α, β, γ, δ)—including 229E, NL63, OC43, HKU1, SARS-CoV, MERS-CoV, HKU20, and IBV—revealed that these coronaviruses share sequence similarity mainly on SF2 and SF5 regions. Furthermore, immunization of female hamsters with COVID19-SF2+SF5 provided significant protection against a SARS-CoV-2 virus challenge. Taken together, our results indicate that vaccination with a protein containing both an receptor binding domain (RBD) region and a common binding region provides strong protection during infection, thus suggesting a potential strategy to avoid evasion of host immune recognition by virus variants. Significantly, the observation that COVID19-SF2+SF5 immunization possesses stronger activity in reducing viral load at early stages suggests that the SF5 region might play an important role in virus recognition and binding to host cells. Based on these findings, we conclude that it is possible to develop universal vaccines and neutralizing monoclonal antibodies to curb the effects of mutations and to target multiple coronaviruses.

Previous studies have highlighted the downregulation of hepatocyte nuclear factor 4alpha (HNF4α) as a critical event in the pathogenesis of HCC. However, the mechanism of its degradation in HCC remains unclear. Tripartite motif 47 (TRIM47), a typical E3 ubiquitin ligase of the TRIM family, has been implicated in various tumors, yet its specific role in HCC progression is not fully elucidated. In this study, HNF4α was identified as a potential target of TRIM47 by using co-immunoprecipitation (Co-IP) combined with mass spectrometry analysis. TRIM47 facilitates the degradation of HNF4α by mediating K48-linked ubiquitination at lysine 470. Abrogation of HNF4α ubiquitination attenuated the promoting effect of TRIM47 on HCC malignancy. Molecular docking studies and Co-IP experiments revealed that K342, W349, and E353 of HNF4α, along with K534 and K600 of TRIM47, are crucial for their interaction. A small molecule, CZ-2401, was selected as a potent inhibitor of the TRIM47–HNF4α interaction through virtual screening and pharmacological activity validation. CZ-2401 effectively stabilizes HNF4α protein in HCC cells and ameliorates TRIM47-driven HCC progression in vivo. Taken together, our research elucidates that targeting TRIM47–HNF4α interaction is a potential therapeutic strategy for HCC, and identifies CZ-2401 as a potent inhibitor of HNF4α degradation and a promising candidate for HCC therapy.

Cold exposure activates brown adipose tissue (BAT), to alleviate metabolic disorders. However, the mechanisms underlying the regulation of mitochondrial lipid droplet contact (MLC) in BAT and their association with these benefits remain unclear. Here, we identify liver-derived β-hydroxybutyrate (BHB) as a key mediator in driving MLC formation in BAT. Mechanistically, BHB directly targets at the GLY-67 residue of RAB10, enhancing its interaction with PLIN5 to form the RAB10–PLIN5 complex, which facilitates MLC. This interaction was validated using SPIDER and biotin-labeled pull-down assays. Functionally, BHB treatment reduces lipotoxicity and improves metabolic health in diet-induced obese mice. These findings establish BHB as a critical link between BAT MLC and the systemic metabolic benefits, highlighting the RAB10–PLIN5 complex as a therapeutic target for obesity and hepatic steatosis. Furthermore, this work underscores the broader significance of cold-induced metabolic adaptations for combating metabolic diseases.

Metabolic reprogramming is a notable hallmark of cancer biology, especially aerobic glycolysis. Some clinical trials attempt to target cancer metabolism to develop therapeutic agents. However, the results have been not satisfactory. Here, we report that REEP6 is significantly upregulated and promotes glycolysis and tumorigenesis in CRC. Moreover, REEP6, as a molecular scaffolder, bridges the PRMT5–PGAM1 complex, which enhances the PRMT5-mediated symmetric dimethylarginine (SDMA) of PGAM1 at R40. The methylated PGAM1 possesses dramatically enhanced enzymatic activity and therefore boosts glycolytic flux in CRC cells. More than that, our results showed that combined treatment with specific shRNA and inhibitors exhibits synergistic anti-tumor efficacy in CRC, which may shed light on the development of a promising therapy in CRC.

Phenylspirodrimanes are a class of structurally diverse meroterpenoids, including the bioactive dimer stachybocin A (1) and the high-reactivity monomer stachybotrydial (2), which are isolated from the genus Stachybotrys. Whereas the biosynthetic pathway of these phenylspirodrimane meroterpenoids has remained elusive. Herein, we deciphered the complete biosynthetic pathway of 2 with unprecedented two gene clusters and five discrete genes by genome mining, gene inactivation, heterologous expression, biochemical experiments, and especially combining with transcriptome-based hierarchical clustering and expression correlation analyses. Totally, 11 genes for the phenylspirodrimane core skeleton formation, 8′-methyl oxidation, and 3-OH epimerization were efficiently discovered and functionally characterized. Notably, these biosynthetic genes are distributed across seven distinct regions, with a rare combination of multiple gene clusters and genes outside the clusters. Bioactivity assays revealed that four intermediates 6-8, and 9a exhibited significant inhibitory effect on the inactivated state hNaV1.2 channels with IC₅₀ values of 0.15, 0.04, 0.28, and 1.91 μmol/L, respectively. These findings expand our understanding of phenylspirodrimane-type meroterpenoid biosynthesis and underscore the utility of transcriptome-based hierarchical clustering and expression correlation analyses for identifying unclustered biosynthetic genes in fungi.

K-RAS mutations represent a most prevalent oncogenic alteration in human cancers. Despite tremendous efforts, it remains a big challenge to develop strategies that specifically target the oncogenic K-RAS mutants. Here, taking advantage of our previous finding that NEDD4-1 is an E3 ubiquitin ligase for wild-type RAS proteins, we developed a compound XMU-MP-9 that can promote ubiquitination and degradation of various K-RAS mutants including K-RASG¹²V, and significantly inhibit proliferation and tumor development of K-RAS mutant harboring cells. Mechanistically, XMU-MP-9 acts as a bifunctional compound to bind the C2 domain of NEDD4-1 and an allosteric site of K-RAS to enhance NEDD4-1 and K-RAS interaction, and to induce a conformational change of NEDD4-1/K-RAS complex to allow NEDD4-1 targeting K128 of K-RAS for ubiquitination. Hence, our study presents an effective way to degrade K-RAS mutants to prevent tumor development.

Perineurally injected nerve-blocking agents have limited capability to cross peripheral nerve barriers (PNBs), requiring high doses to block pain signals on axons. This increases the risk of local tissue toxicity and systemic side effects on the cardiovascular and neurological systems. To address this, we explored carboxyl group modification to enhance the permeability of nerve-blocking agents across the PNBs through carrier-mediated transport facilitated by monocarboxylate transporters (MCTs). The enhanced permeability allows for targeted drug delivery to peripheral nerve axons, resulting in a significant reduction in the necessary drug dosage for a long-lasting nerve block. Specifically, we developed a carboxylated prodrug of capsaicin (COOH-CAP) by conjugating it with a carboxyl group via a degradable ester bond. Calcium flux assays, patch-clamp recordings, and body temperature measurements collectively confirmed that COOH-CAP activates TRPV1, with potency comparable to capsaicin. In rats, a single sciatic nerve injection of 3.28 μmol COOH-CAP produced a nociceptive-selective nerve blockade lasting 260 ± 83.7 h without motor impairment or capsaicin-related side effects, approximately 35 times longer than the same dose of plain capsaicin. Even at a lower dose of 1.64 μmol, COOH-CAP still produced nociceptive-selective nerve blockade for 172.0 ± 41.3 h.

Hyperimonates A (1) and B (2), two minor polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented hexahydro-1H-cyclopenta[c]furan-1-one and 2-oxabicyclo[2.2.1]heptane ring system were isolated from Hypericum monogynum. To obtain adequate materials for biological research, the asymmetric total syntheses of 1 and 2 were completed from commercially available geraniol via a bioinspired strategy that features an Au(I)-catalyzed carbometallic cascade cyclization and a Mn(III)/Cu(II) mediated oxidative radical cyclization as vital steps. Biological study implied that compound 1 showed excellent lipid-lowering activity in vitro via inhibiting two signaling pathways, Notch and PPAR, further verified by non-alcoholic fatty liver disease (NAFLD) zebrafish model. These findings provide a new structural template for the treatment of NAFLD and asymmetric synthetic approaches could also facilitate further evaluation for drug development.

The modulation of tumor autophagy to enhance antitumor immunity has garnered significant attention, underscoring its critical role in cancer immunotherapy. However, advanced strategies for precise autophagy-regulating drug delivery remain a pressing need. Here, we introduce a targeted small extracellular vesicles (sEVs)-based drug delivery system capable of simultaneously loading antibodies and nucleic acid drugs while ensuring their accurate release in the tumor microenvironment (TME). We developed a dual-stimulation electroporation system that integrates nanosecond electric pulses and ultrasound to enhance sEV production, yielding IL-7 mRNA-enriched sEVs that overexpress CD64 receptors for efficient capture of anti-PD-L1 antibodies. These multifunctional autophagy-inhibiting and immunomodulatory sEVs (AI-sEVs) are designed to inhibit autophagy and modulate immune responses in non-small cell lung cancer. Upon delivery to the TME, AI-sEVs mediate the enzymatic cleavage of peptide bonds, releasing IL-7 mRNA. This process induces autophagy suppression and restores MHC-I expression, which synergizes with anti-PD-L1 immune checkpoint inhibition to enhance antitumor efficacy. In conclusion, this study proposes an innovative methodology that utilizes engineered sEVs for the co-delivery of protein antibodies and genetic materials. This approach establishes a promising strategy for advancing cancer immunotherapy by targeting the modulation of autophagy.

Despite remarkable achievements in antibody-drug conjugates (ADCs), payloads remain limited. The identification of ADC payloads with novel mechanisms will increase therapeutic options and expand indications. Herein, we describe the use of dihydroorotate dehydrogenase inhibitors (DHODHi) as a novel payload class that provides highly potent ADCs for antitumor and antiviral therapies. Technical innovations include the development of stability-controllable linkers to meet the distinct requirements of acute viral infections and chronic tumor conditions. The antitumor ADC TH-C8H exhibited significant efficacy against gastric cancer in vivo as monotherapy and enhanced efficacy when combined with the ferroptosis inducer RSL3. The antiviral ADC HG-C3 showed broad-spectrum anti-SARS-CoV-2 activity in vitro and in vivo. Our study expands the types of ADC payloads and provides novel insights into the development of innovative broad-spectrum ADCs.

Studies have shown that radiotherapy (RT) has powerful immune-stimulating effects. However, RT-mediated distal tumor regression is rare in clinical practice. Here, with an animal experimental model, we found that RT shaped an immunosuppressive landscape characterized by a high-influx of myeloid-derived suppressor cells (MDSCs), and the induction of immunologically silent tumor apoptosis, hindering the efficacy of radioimmunotherapy. To address this issue, we developed a spatiotemporally controlled nanomedicine for remodeling the immunosuppressive tumor microenvironment (TME) post-RT. Decitabine (DAC)-loaded ferritin (Ft) were crosslinked via an azobenzene linker, and meanwhile encapsulated with all-trans retinoic acid (ATRA) to construct a Ft@DAC@ATRA nanoassembly (denoted as FD@ATRA), which dissociated into monodispersive Ft@DAC units in hypoxia TME. The released ATRA could eliminate immunosuppressive MDSCs, and meanwhile Ft@DAC selectively induced immunogenic pyroptosis of the tumor by targeting the transferrin receptor 1 overexpressed on the tumor to effectively activate CD8⁺ T cells. FD@ATRA treatment reshaped the tumor immune landscape post-RT with an increase of 16.8% in tumor-infiltrating IFN-γ⁺CD8⁺ T cells. Moreover, FD@ATRA-enhanced RT remained effective in large, treatment-resistant tumors, and the inhibition rate of FD@ATRA-enhanced RT on distant tumors improved by 47% compared to the RT group alone, providing an effective therapeutic approach to improve the clinical outcomes of radioimmunotherapy.

The mild photothermal therapy of solid tumors was still bottlenecked by the uneven temperature distribution in tumor tissue and the autophagy-mediated resistance. Here, we leveraged the ultra-small size (approximately 0.32 nm) and autophagy inhibitory property of nitric oxide (NO) to overcome these limitations for enhanced gas-photothermal therapy of large tumors. An NO donor was loaded into mesoporous polydopamine and coated with tumor cell membranes for tumor-targeting delivery. The acid-triggered release of NO potently inhibited autophagy to block the pro-survival pathway of tumor cells. Besides, as a small-molecule gas, it diffused freely into deep regions and precisely eliminated the deep-seated tumor cells, resulting in approximately 90% tumor inhibition in the late-stage breast tumor model (>500 mm³). The NO gas therapy shows great potential for complementing other therapeutics for the synergistic therapy of large solid tumors.

The intratumoral microbiome plays a crucial role in cancer progression, prompting the development of therapies targeting it. However, due to the heterogeneous effects of intratumoral microbes, designing treatments tailored to the unique microecological characteristics of individual tumors poses a significant challenge. Here, we found significant variations in the abundance of five bacterial genera—Lysinibacillus, Stenotrophomonas, Weissella, Comamonas, and Aeromonas—between lung adenocarcinoma (LUAD) and normal tissues by analyzing single-cell transcriptomic datasets. These specific bacterial clusters were significantly associated with immune infiltrates in the tumor microenvironment (TME). After confirming their effects in mouse models, these bacterial taxa were identified as potential therapeutic targets. Through in vitro drug screening assays, berberine was identified as a promising agent that selectively inhibits harmful bacteria while sparing beneficial ones. To address berberine’s low solubility and tumor targeting issues, it was encapsulated into tumor cell-derived extracellular vesicles (EV-ber). Feature analysis demonstrated that EV-ber shifted the intratumoral microbiome profile toward an anti-tumor phenotype and enhanced anti-tumor immunity in the TME. Furthermore, EV-ber administration inhibited LUAD growth, impaired LUAD metastatic ability, and boosted the effectiveness of anti-PD-L1 immunotherapy in mouse models. In conclusion, this work demonstrates the potential of personalized intratumoral microbial re-education strategies in LUAD therapy.

Interference with calcium homeostasis provokes tumor cell death and immune response, providing a novel direction for tumor immunotherapy as a promising cancer treatment strategy. Nevertheless, most reported Ca²⁺-overloaded nanoinducers encounter challenges such as intricate preparation procedures, safety concerns arising from inorganic material input, and limited anti-tumor efficiency. Herein, we synthesized a biocompatible and pH-sensitive Ca-doped cyclodextrin metal-organic framework (Ca/K-MOF) as a carrier, which was then loaded with photosensitizer hypericin (HY) via a simple one-pot synthesis to form HY@Ca/K-MOF. To enhance the stability both in vitro and in vivo, we coated HY@Ca/K-MOF with a hydrophilic layer of PEG (PEGHY@Ca/K-MOF). When exposed to 590 nm photoirradiation, PEGHY@Ca/K-MOF, with its pH-responsive dissociation, the Ca²⁺ and HY mediators released at the tumor site share the responsibility of triggering intracellular Ca²⁺ disturbances, which amplified the production of reactive oxygen species (ROS) and led to mitochondrial calcium overload through modulating mitochondrial MICU1 function. Under photocontrol, this interplay between ROS generation and mitochondrial calcium overload created a bidirectional amplification effect, where each process reinforced the other, subsequently eliciting a pyroptosis-evoked immune response. Significantly, this newly constructed delivery platform effectively suppressed both primary and distant tumors without the need for additional immunological interventions. In summary, this Ca²⁺-doped MOF-based nanomaterial provides a promising approach for efficient tumor photo-controlled mitochondrial Ca²⁺ overload-pyroptosis immunotherapy.

Transdermal drug delivery relies heavily on the skin permeability of therapeutic agents. In order to develop a peptide-based delivery strategy for promoting transdermal absorption, the key physicochemical factors influencing skin permeability are first identified through cell-penetrating peptides (CPPs) screening and computational simulation. Penetratin exhibits the most outstanding permeability and safety among CPPs from various origins, and positive surface patch area emerges as the key property correlated with skin permeability of the peptides. Based on these findings, a precise model to predict skin permeability of the peptides is established, leading to the computational redesign of penetratin’s amino acid sequence. The transdermal delivery efficiency of optimized penetratin derivative (589WP) is significantly improved in vitro compared with wild-type penetratin and visualized through in vivo imaging. Furthermore, the anti-metabolic drug floxuridine (FUdR) is covalently conjugated with 589WP via ester linkage, leading to accelerated FUdR release due to esterase degradation. Subsequently, this conjugate is formulated into an anhydrous gel, which significantly inhibits melanoma growth with topical application, outperforming a higher dose of free FUdR without observed skin irritancy or toxicity. The peptide prediction and design approaches established herein hold great potential for advancing transdermal drug delivery.

Profiling in vivo release kinetics of drug nanocarriers is of high translational significance. However, this has remained unrealized due to the lack of direct methodologies to quantify either the total released or residual drugs. This study employed an indirect strategy, comparing pharmacokinetics and particokinetics, to estimate the in vivo release kinetics of paclitaxel (PTX) from intravenously administered mPEG-PDLLA polymeric micelles (PMs). Blood pharmacokinetics were profiled by chromatographically quantifying PTX, while particokinetics were determined following labeling PM particles by near-infrared fluorophores with aggregation-caused quenching properties. By monitoring the dynamic change in the PTX-to-copolymer ratio, the in vivo release of PTX from the PMs was estimated. The results revealed surprisingly rapid release, with over 88.2% and 99.0% of PTX released by 15 s and 5 min post-administration, respectively. It is concluded that PTX is released rapidly from PMs in vivo, and PMs may merely work as “solvents” to solubilize PTX rather than as carriers for targeted delivery.