Carbon monoxide (CO)-involving gas therapy, with advantages of high transmembrane diffusivity, multiple pharmacodynamic functions, and non-resistance, holds tremendous potential in cancer therapeutics. However, the main challenges of medicinal CO come from poor tumor targeting and high toxicity. The development of stimuli-responsive CO-releasing molecules (CORMs) enables controlled CO release and reduced gas poisoning. Particularly, advancements in stimulus-ignited nanogenerators built on CORMs create new avenues for precision targeting of malignant tumors and gas-sensitized synergistic therapy. This review initially elucidates the association between CO and tumor progression, and discusses the significance of designing stimulus-ignited CO nanogenerators from the perspective of the dilemma and opportunity of CO treatment. Then, the applications and rationale of CO nanogenerators in spatiotemporally targeted cancer therapy are outlined from different stimulation modalities, highlighting the recent advancements and their primary synergistic effects with other cancer therapeutic paradigms. Finally, the challenges and possibilities of the emerging CO nanogenerators for cancer gas therapy are discussed. This review elucidates the design strategy of stimulus-responsive CO nanogenerators and their synergistic mechanism in precision tumor therapy, which lays down a theoretical framework for the paradigm shift of CO from lethal toxin to therapeutic agent.

Epilepsy remains a major neurological disorder characterized by unpredictable seizures and cumulative comorbidities that even endure with standard pharmacotherapy. Conventional antiepileptic drugs (AEDs) are constrained by two interrelated barriers: limited brain penetration due to the blood-brain barrier (BBB), which necessitates high systemic dosing and peripheral toxicity, and a narrow mechanistic focus on neuronal ion channels and synaptic receptors. This neuron-centric view overlooks non-neuronal drivers, such as neuroinflammation and BBB dysfunction, that sustain epileptogenesis and contribute to drug resistance in roughly one-third of patients. Nanomedicine addresses these limitations through a fundamentally different approach. Leveraging the unique advantages of nanocarriers, including facile synthesis, surface modification, and receptor-mediated BBB transcytosis, nanoparticles have evolved from passive delivery vehicles into intelligent, multifunctional therapeutic platforms that actively engage with disease biology. In this Perspective, we first delineate the inherent limitations of conventional AEDs in target selection. We then highlight how emerging nanomedicines are expanding the therapeutic target repertoire to include key non-neuronal nodes, with a focus on neuroinflammation and BBB repair. Finally, we offer a forward-looking perspective on two emerging frontiers: modulation of metabolic dysregulation and the microbiota-gut-brain axis, as well as the development of theranostic nanoplatforms that integrate real-time seizure monitoring with closed-loop intervention. Through this discussion, we aim to inspire a reorientation of nanomedicine strategies toward precision therapy for epilepsy.

Strategies that reduce dependence on synthetic pesticides while maintaining crop productivity are increasingly emphasized in sustainable agriculture. Here, we developed a bioinspired plant protein-based delivery system consisting of quercetin-loaded soy protein isolate (SPI)-zein nanocapsules. Spray drying was employed as a structural engineering strategy to assemble and immobilize nanocapsules into pomegranate-like hierarchical particulate aggregates. SEM, fluorescence spectroscopy, FT-IR, UV-vis spectroscopy, XRD and TGA were employed to characterize quercetin-loaded SPI-zein systems prepared at different SPI:zein ratios. Structural and morphological analyses revealed spherical nanocapsules embedded within interconnected protein aggregates. The formulation with an SPI:zein ratio of 1:2 exhibited the best overall performance, including an encapsulation efficiency of 75.2%, loading capacity of 3.23%, pH-responsive release behaviour, enhanced rainfastness, and improved photochemical and storage stability. Notably, pre-spray-dried nanocapsule dispersions did not significantly improve rainfastness or photoprotection, whereas the spray-dried hierarchical structures exhibited enhanced resistance to wash-off under rainfall conditions, improved protection against UV-induced quercetin photodegradation, and more sustained quercetin release. These findings highlight the functional importance of the engineered pomegranate-like hierarchical architecture. Furthermore, biological assays using pea seedlings (Pisum sativum L.) and black bean aphid (Aphis fabae) demonstrated effective pest deterrence and promotion of plant growth. Our delivery system represents a promising platform for dual-function agrochemical delivery.

Neutrophil extracellular traps (NETs) may facilitate metastasis of tumor cells through interaction with the CCDC25 located along cell membrane, resulting high mortality of patients. Although cationic materials can destruct NETs and inhibit tumor metastasis, they lack targeting ability in physiological environments. Herein, we designed and synthesized a peptide-dendrimer conjugates, AAPVRnS(5-n)-G2.5, that may target neutrophil elastase (NE), a component of NETs, expose their cationic cores by NE degradation, and finally neutralize DNAs of NETs via charge interaction. It combined a triple strategy: the AAPV tetrapeptide sequence provides targeting ability to NET-enriched regions; the arginine (R) and serine (S) segment ensures DNA binding efficacy as well as biocompatibility; and the PAMAM-G2.5 dendrimer provides multivalent effect and an extended circulation. The characterization shows that AAPVRnS(5-n)- G2.5 has NET targeting and NE responsiveness, and the obtained RnS(5-n)- G2.5 after NE treatment shows an enhanced zeta potential and DNA binding ability. In turn, the cationic RnS(5-n)-G2.5 can destroy NETs, competitively block the binding between NET-DNA and CCDC25, and then inhibit NET-induced tumor cell cytoskeleton remodeling. In vivo, the conjugates prolong the circulation half-life of the materials and promote the enrichment in organs prone to metastasis. In the 4 T1 orthotopic breast cancer mouse model, AAPVR4S1-G2.5 shows the best performance, significantly reducing the level of NETs in the lung and liver, and inhibiting tumor metastasis without causing obvious toxicity. This NET targeted and NE responsive conjugate materials provide an alternative strategy for precise inhibiting tumor metastasis.

Drug delivery using self-assembling drug-excipient nanoparticles offers a scalable strategy to improve the solubility, bioavailability, and biodistribution of poorly soluble therapeutics. However, progress in the development and translation of these materials has been limited by the lack of safe excipients capable of stabilizing drug-rich nanoparticles that allow for extrahepatic delivery. Here, we present an adaptive machine learning-guided workflow for excipient discovery that prospectively prioritizes candidate dyes and identifies clinically relevant drugs compatible with dye-based nanoparticle formulations. Guided by model predictions, we deployed semi-automated synthesis together with in vitro and in vivo experimental validation to evaluate and characterize the resulting nanoparticles. We identified two FDA-approved dye excipients and rediscovered a third dye as favorable excipients. Fine-tuning our machine learning models enabled us to identify 35 previously unreported nanoparticle formulations utilizing these dyes. Importantly, in proof-of-concept in vivo biodistribution studies, these dye excipients enabled the encapsulation of the anticancer drug sorafenib with distinct extrahepatic biodistribution profiles, including preferential accumulation in the lung. Taken together, this work establishes an adaptive machine learning-driven framework for excipient discovery and demonstrates that small-molecule dye excipients can serve as modular regulators of nanoparticle biodistribution. These findings expand the molecular and computational toolboxes for drug-excipient nanoparticle design and prototype the excipient selection process as a potentially powerful strategy to tune in vivo drug delivery.

Myeloid differentiation primary response protein 88 (MyD88) is an intracellular signaling molecule that is a central mediator of inflammation. MyD88 mediates inflammation in the foreign body response (FBR), a complex immune reaction triggered by implanted biomaterials that leads to fibrous encapsulation. Inhibiting MyD88 offers a promising approach to combat the FBR. A stimuli-responsive therapeutic poly(ethylene glycol) (PEG) hydrogel was developed to release a small molecule inhibitor of MyD88 (T6167923) when cleaved by matrix metalloproteinase 12 (MMP-12). MMP-12, also known as macrophage elastase, is produced primarily by macrophages, the immune cells that are responsible for the FBR. The therapeutic hydrogel was designed by modifying T6167923 with a free thiol (T6167923(SH)) enabling its immobilization into a hydrogel via a PEG spacer to increase its solubility once released and with a peptide linker PLGLEEA known to be sensitive to MMP-12. The bioactivity of free T6167923(SH) in solution was first confirmed in murine macrophages in vitro, leading to a dose-dependent inhibition of NF-κB activation and pro-inflammatory cytokine (IL-6 and TNF-α) production. Once tethered and released from the hydrogel, the released inhibitor is linked to the PEG spacer and the amino acid sequence PLG (i.e., Inhibitor-PEG-PLG). As MyD88 inhibition occurs intracellularly, cell uptake of the inhibitor was confirmed but the efficacy decreased with increasing length of PEG. Thus, a small PEG12 linker was chosen to design the therapeutic hydrogel. MMP-12 diffusion through the hydrogel network was confirmed, which successfully cleaved the MMP-sensitive sequence enabling release of a payload. The therapeutic hydrogel was subcutaneously implanted in mice, leading to a 50% decrease in the inflammatory cell layer thickness relative to the non-therapeutic PEG hydrogel control at day 7. By day 28, the thicknesses of the inflammatory cell layer and the fibrous capsule were reduced by 74% and 61%, respectively, relative to hydrogel implants without tethered inhibitor. In summary, this study demonstrates a promising novel therapeutic hydrogel that is capable of attenuating inflammation when triggered by macrophage elastase.

Postoperative biochemical recurrence and local tumor relapse remain major clinical challenges in managing prostate cancer. Here, we report an injectable and sprayable supramolecular paclitaxel prodrug nanofiber (PF) co-loaded with a potent androgen receptor inhibitor darolutamide (ODM) for long-acting chemo-hormonal therapy against prostate cancer. Upon spraying, ODM/PF rapidly undergoes in situ gelation, forming a uniform hydrogel depot that coats irregular surgical surfaces and enables sustained, controlled drug release in response to the reductive tumor microenvironment. This dual-acting chemo-hormonal strategy produces potent therapeutic synergy by combining paclitaxel-induced mitotic arrest and apoptosis with suppression of androgen receptor signaling. In a murine model of incomplete tumor resection, postoperative spraying of ODM/PF effectively prevented local recurrence, significantly outperforming either agent alone while maintaining a favorable systemic safety profile. Our findings establish ODM/PF as an immediate postoperative adjuvant platform that maximizes local drug concentrations, minimizes systemic exposure, and enables early control of potential residual disease, thereby substantially reducing the likelihood of tumor recurrence.

The gut-liver-kidney (GLK) network is a critical driver of type 2 diabetes mellitus (T2DM) complications, where gut dysbiosis triggers cycle of hepatic metabolic stress and subsequent renal dysfunction through a complex, bidirectional signaling crosstalk. Despite its importance, therapeutic strategies capable of addressing this multi-organ crosstalk remain elusive. Here, we demonstrate that bivalent functionalized curcumin-encapsulating PLGA nanoparticles (nGA2-CUR) combined with subcutaneous insulin beneficially modulate the GLK network in obese T2DM mice. This combination therapy successfully stabilized systemic glucose homeostasis and restored essential endocrine signaling (insulin, GLP-1, and GIP) while significantly suppressing pro-inflammatory markers (MCP-1, haptoglobin). Microbiome profiling revealed a suppression of pathobionts alongside distinct sex-specific restorative responses, where males exhibited Muribaculaceae enrichment while females showed Bifidobacterium expansion. Integrated liver metabolomics associated these microbial shifts with unique organ-specific repair responses in each sex. Males showed elevated levels of purine salvage pathway intermediates alongside suppression of a specific pathobiont cluster (including Lautropia and Porphyromonas) correlated with oxidative stress, whereas females replenished aromatic amino acids, consistent with reduced predicted microbial proteolytic potential and lower markers of nephrotoxic uremic toxin production. Molecular analysis confirmed the downregulation of glucose-sensitive pathways (Chrebp/Srebp-1c). These systemic improvements were accompanied by an anti-inflammatory M2 macrophage profile shift, alongside suppression of renal fibrosis via the TGFβ/SMAD network and reduced injury markers (Cystatin C and Osteopontin). Our findings suggest that by reshaping the gut microbiome to alleviate upstream hepatic metabolic burden, this nanoparticle-enhanced therapy provides a sex-specific framework for attenuating irreversible diabetic renal injury.

Localized therapy via oral drug delivery remains particularly challenging for inflammatory bowel diseases (IBD) due to the distinct anatomical and pathophysiological features of the colonic region in the gastrointestinal (GI) tract. Despite extensive exploration of diverse formulation strategies for IBD management, clinical translation has remained limited, resulting in a paucity of effective oral treatment options. This review integrates current mechanistic insights into colon-specific immune pathophysiology with emerging trends in oral formulation development. All of which underscores the urgent need for advanced formulation strategies that integrate multiple targets for IBD treatment.

In endodontic procedures, the elimination of bacteria from the complex root canal system is crucial for ensuring the overall success of treatment. Given that commonly employed irrigation solutions lack sustained antimicrobial activity and that intracanal medicaments are difficult to remove and may adversely affect the dentinal microstructure, a highly flexible antimicrobial poly(ethylene-co-vinyl acetate) (PEVA) implant was developed as an alternative strategy for eradication. On the basis of a screening of various PEVAs for optimal properties, implants were prepared via ram extrusion with fine-tuning of their diameters (0.3-1.5 mm) to satisfy application demands. Along with a comprehensive assessment of physicochemical properties, a demonstration of the controlled release of gentamicin from implants of various diameters, and ex vivo implantation experiments, an in vivo study of a Galleria mellonella larvae model demonstrated the effectiveness of antimicrobial implants against Enterococcus faecalis on the basis of survival data. Overall, the here reported dental implants can be considered for future temporary infills and should next be evaluated under multispecies biofilm conditions.

Targeting lipid metabolism reprogramming presents a potential strategy to overcome drug resistance and enhance treatment outcomes in pancreatic cancer. Caveolin-1, a critical regulator of lipid metabolism, is highly expressed in pancreatic cancer, indicating its viability as a novel therapeutic target. To address the poor biocompatibility and inadequate tumor targeting associated with methyl-β-cyclodextrin (MβCD)-an indirect inhibitor of Caveolin-1 function through cholesterol chelation-novel MβCD@hyaluronic acid-adamantane (MβCD@HA-Ad) nanoparticles were developed to enhance therapeutic efficacy against pancreatic cancer. These nanoparticles achieve dual targeting via HA-mediated CD44 receptor binding and MβCD-driven Caveolin-1 metabolic inhibition, while exhibiting acid-responsive release properties that enhance their responsiveness to the pancreatic cancer microenvironment. In vitro studies suggest that MβCD@HA-Ad nanoparticles possess improved drug penetration capacity and enhanced antitumor effects. Inhibition of Caveolin-1 induces cell membrane stretching and increases Piezo1 sensitivity to mechanical stimuli, resulting in elevated intracellular Ca[2+] influx, activation of PLA2G4A phosphorylation, and subsequent promotion of lipolysis. Concurrently, impaired endocytosis reduces fatty acid uptake, resulting in decreased lipid droplet accumulation. Non-targeted metabolomics analysis indicates that Caveolin-1 regulates glycerophospholipid and fatty acid metabolism in pancreatic cancer cells, influencing cellular growth, migration, and invasiveness. In a mouse model of pancreatic cancer, MβCD@HA-Ad nanoparticles exhibited excellent biosafety, efficient tumor-targeting capabilities, and sustained antitumor effects. By reducing lipid deposition in tumor tissues, these nanoparticles significantly delayed tumor progression and inhibited tumor cell proliferation. In summary, MβCD@HA-Ad nanoparticles exert precise antitumor effects by targeting Caveolin-1 and modulating the Piezo1/PLA2G4A signaling axis to disrupt lipid metabolism, thereby presenting a novel nanotherapeutic strategy for pancreatic cancer.

The secretome of mesenchymal stromal cells (MSCs) has emerged as a promising cell-free therapeutic strategy for regenerative medicine and immune modulation. However, its clinical translation remains limited by restricted stability and the short in vivo half-life of its bioactive factors, often requiring repeated administrations. Here, we describe an injectable star-shaped poly(ethylene glycol)-heparin (starPEG-heparin) hydrogel that enables the stable loading and sustained release (up to 14 days) of a lyophilized immunomodulatory MSC secretome (LS). Controlled delivery resulted from the interplay between LS-derived protease-driven hydrogel degradation and bioactive factor affinity to the heparin building block. Release studies showed sustained liberation of regenerative, immunomodulatory, and matrix-modulating factors, including VEGF, PDGF-AA/BB, IL-1Ra, IL-4, IL-10, Gal-9, and TIMP-1, yielding a compositionally balanced release profile over time. Importantly, hydrogel-released LS preserved robust bioactivity for 14 days, inhibiting ConA-induced PBMC proliferation and partially repolarizing M1 macrophages toward an anti-inflammatory phenotype (reduced CD86 and increased CD209/CD163). These results demonstrate that starPEG-heparin hydrogels maintain LS stability and immunomodulatory bioactivity in vitro for up to two weeks, supporting their use as controlled-release matrices for MSC-derived secretome-based approaches.

Phase-change perfluorocarbon nanodroplets (PCND) are nanoscale carriers that can be vaporized acoustically to form echogenic microbubbles. This enables ultrasound-triggered imaging and therapy to extend beyond the intravascular space. Despite being extensively studied, their in vivo pharmacokinetics have been reported inconsistently and direct comparisons between formulations are lacking. This limits rational formulation design and translation. Thus, we developed a formulation-property-function framework by systematically decoupling core volatility, shell composition and particle size of protein- and lipid-coated PCND with C5F12 or C6F14 cores and mean diameters of ∼200 and ∼ 300 nm. Across formulations, physicochemical properties, including stability, mechanical deformability and acoustic vaporization threshold, were found to be formulation dependent. These properties, in turn, influence acoustic vaporization, tolerated dose and in vivo pharmacokinetics. Notably, larger or protein-coated PCND exhibited lower acoustic vaporization thresholds, but had lower tolerated doses, shorter circulation half-lives and reduced tumor accumulation. Conversely, smaller or lipid-coated PCND demonstrated improved tolerability, prolonged circulation and greater tumor retention, though they required higher acoustic pressures for vaporization. Additionally, shell mechanics governed PCND deformability, likely influencing their circulation and ability to traverse microvascular constrictions. Tumor accumulation was therefore shaped by both formulation properties and tumor vascular architecture. Formulations with greater stability, deformability, and prolonged circulation accumulated even in less permissive vasculature, whereas formulations with lower stability and shorter circulation required higher vascular permeability for detectable delivery. Overall, we provide a mechanistic framework for PCND design that links formulation parameters to their pharmacological profile and balances vaporization efficiency with in vivo performance and dose tolerability.

Critical-sized bone defects pose a significant clinical challenge, with inadequate blood supply being a major factor impairing bone healing. In the initial stage of bone healing, the blood clot acts as a "natural glue," serving not only as a scaffold for stem cell growth but also providing a reservoir of cytokines and growth factors that regulate and reconstruct the osteogenic microenvironment. In this study, we hierarchically integrated platelet concentrates with distinct functions into an injectable thermosensitive hydrogel, constructing a "biomimetic blood clot" system. First, leukocyte-platelet-rich fibrin (L-PRF) lyophilized powder, which promotes the osteogenic differentiation of periosteum-derived mesenchymal stem cells (PMSCs), was incorporated into methacrylated gelatin hydrogel microspheres (GM) to form GM[L-PRF]. Subsequently, advanced platelet-rich fibrin (A-PRF) lyophilized powder, which enhances the angiogenic differentiation of lamina propria-derived mesenchymal stem cells (LMSCs), was blended into a hydrogel precursor composed of chitosan (CS), polygalacturonic acid (PgA), β-glycerophosphate (β-GP), and GM[L-PRF]. This yielded a thermosensitive hydrogel, designated CSPgA[A-PRF]GM[L-PRF] (CP[A]G[L]), which exhibits favorable mechanical properties at 37 °C and enables the programmed release of growth factors from both A-PRF and L-PRF. The CP[A]G[L] hydrogel could induce the differential differentiation of distinct types of MSCs. It facilitates vascularized bone regeneration by activating the JAK2-STAT3/HIF-1α and the TGF-β/Wnt signaling pathway, thereby effectively initiating the coupled angio-osteogenic process. In summary, the biomimetic blood clot system CSPgA[A-PRF]GM[L-PRF] represents a potential injectable biomaterial strategy for bone defect repair.

Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for targeted protein degradation but suffer from poor solubility, bioavailability, and in vivo distribution due to their "beyond rule-of-five" physicochemical properties, severely limiting clinical translation. Here, we transform these intrinsic drug-likeness liabilities into a driving force for molecular self-assembly by developing a carrier-free nanoplatform in which PROTACs spontaneously co-assemble with cyanine dyes, including IR783 and the clinically approved indocyanine green (ICG). This strategy generates stable supramolecular assemblies with ultra-high PROTAC loading (up to 70 wt%) without the need for exogenous carriers, while imparting intrinsic NIR fluorescence for real-time, non-invasive in vivo tracking. The assemblies undergo stimuli-responsive disassembly upon ultrasound or X-ray irradiation, enabling spatiotemporally controlled PROTAC release within tumors. Incorporation of diselenide-bridged cyanine derivatives further confers radiosensitization capability, allowing synergistic combination with radiotherapy. In vivo studies demonstrate efficient tumor accumulation, robust target protein degradation, and potent antitumor efficacy. Collectively, this work establishes a versatile supramolecular strategy that directly addresses the long-standing delivery challenges of PROTACs and advances precise, controllable oncological therapy.