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The understanding of the “enhanced permeability retention” (EPR) effect which enables cancer nanocarriers to penetrate solid tumors remains controversial. Here this group evaluates a range of intravenously injectable lipid-coated mesoporous silica nanoparticles exploring the role of proteins attached to the surface of nanoparticles in transcytosis-dominant cancer drug delivery.

In this study, the authors present optimization and efficacy testing of apolipoprotein-based lipid nanoparticles for delivering various nucleic acid therapeutics in vivo to immune cells and their progenitors in the bone marrow.

The relationship between pancreatic β-cell dysfunction and autoinflammation in T2DM is unclear. Here, the authors show the key role of a UCP2/mtDNA/STING axis in the IL-1β induced autoinflammation cycle in T2DM and develop Mito-G, a highly efficient mitochondria targeting nanodrug to treat T2DM.

Diabetic wounds are a prevalent type of chronic wound that is challenging to treat due to the dynamic and complex wound microenvironment. Here, Cong et al. presents a dimeric copper peptide incorporated hydrogel for multifunctional treatment of diabetic wounds.

The combinatorial synthesis of ionizable lipids allows for the identification of an antioxidant lipid exhibiting low immunogenicity for lipid nanoparticle-mediated mRNA delivery in vivo.

A remora-inspired mechanical underwater adhesive device adheres securely to a range of soft substrates and maintains performance under extreme pH and moisture conditions, with potential applications in biosensing and drug delivery.

An antibody–polysialic acid conjugate induces calcification on the surface of methicillin-resistant Staphylococcus aureus and boosts immunogenicity in mice.

Lipid nanoparticles (LNPs) are a promising platform for mRNA delivery, but their use in inflammatory pulmonary diseases is limited by reactogenicity and suboptimal delivery. Here, the authors report a VATPase activating non-inflammatory LNP (NIF-LNP) exhibiting a 40fold enhancement in lung protein expression without causing significant reactogenicity compared to commercial LNPs.

Tyrosinase (TYR) catalyses the two initial steps of melanin synthesis from tyrosine and is a target in developing therapeutics to treat melanin-associated disorders. Here, the authors devise a TYR-based in situ catalytic platform that can generate drugs intracellularly through an endogenous copper-catalysed azide-alkyne cycloaddition reaction, as well as a TYR-catalysed in situ formed proteolysis-targeting chimeras to degrade intracellular TYR protein and decrease melanin synthesis for treating hyperpigmentation.

RNA interference therapy has huge potential in pesticide applications, however delivery and stability remain an issue. Here, the authors report on a metal-organic framework, polydopamine nanoparticle for increasing delivery and stability of RNA to plants. Demonstrating application in targeting the fall armyworm.

Poly(carboxybetaine) lipids enhance mRNA lipid nanoparticles efficacy and reduce their immunogenicity, being promising alternatives to poly(ethylene) glycol lipids used in traditional mRNA lipid nanoparticle formulations.

ZF5.3 is a mini-protein that escapes endosomes efficiently. Work to understand the underlying mechanism now reveals that ZF5.3 unfolds at pH values lower than 5.5 through protonation of Zn(II)-bound His residues. Unfolding promotes pH-dependent interactions with a unique lipid present in late endolysosomal membranes and is essential for endosomal escape.

NCOMMS-24-82016B Macrophages play essential roles in the progression and rupture of atherosclerosis. Here, the authors report an adaptable platelet-protein platform tailored for the targeted delivery of both antioxidant nanocatalysts and TRAF6 inhibitor to advance synergistic therapy for atherosclerosis.

Photothermal therapy using photo agents developed with high photothermal conversion efficiency under long-wavelength laser irradiation has been investigated in preclinical cancer treatment. Here this group reports coating mesoporous carbon nanomaterials with a lanthanide oxysulfide up-conversion material (Y₂O₂S:Yb³⁺, Er³⁺) with tumor targeting capability for in situ ocular melanoma tumor treatment.

A wireless, minimally invasive emergency rescue device is developed for the active burst-release of stable particulate forms of peptide and hormone drugs into subcutaneous sites in mice.

Transarterial chemoembolization (TACE) is a common clinical intervention used for unresectable liver tumors, but conventional embolic microspheres generally exhibit slack vascular stacking and suboptimal drug release. Here, Guo et al. report tumor vessel-adaptable, adhesive, and absorbable microspheres (3Asphere) for sustained TACE therapy of liver tumors.

Depletion of circulatory asparagine (Asn) by L-asparaginase (ASNase) has been used for clinical treatment of leukemia. Here this group develops core-shell structured cascade-responsive nanoparticles for sequential modulation of exogenous Asn supply and endogenous Asn production, thereby achieving the amino acid depletion therapy against solid tumors.

On-target, off-tumour toxicity is a major concern in immunotherapy. Here, aided by computer docking analysis, the authors introduce a single oxygen atom into the TLR7/8 agonist R848, generating a radiotherapy-activatable prodrug agonist that in mice helps mitigate systemic toxicity while triggering effective anti-tumor immunity responses upon radiation.

Ferroptosis immunotherapy is promising for treating triple-negative breast cancer, but hindered by limited iron levels in tumor cells and a lack of specific immune responses. Here, the authors report a biohybrid system that enhances iron level by activating endogenous iron ions and replenishing exogenous iron ions and targets ferritin for synergistic ferroptosis immunotherapy.

Hydrogel materials have emerged as versatile platforms for biomedical applications. Here this group reports an mRNA lipid nanoparticle-incorporated microgel matrix for immune cell recruitment/antigen expression and presentation/cellular interaction thereby eliciting antitumor efficacy with a single dose.

In this work the authors develop PACES (protein-assembly complex for elimination system) which uses cell-selective nanofibers with bioorthogonal decoration of an E3 recruiter to trap and degrade proteins. This strategy complements PROTACs and PPI-based approaches, expanding the degradable proteome.

The development of subunit vaccines mimicking the molecular complexity of attenuated vaccines has been limited by the difficulty in co-delivery of multiple chemically diverse payloads. Here, the authors report hierarchical hydrogels, assembled from a single homopolymer via a multi-stage process, that enable ratiometric loading of a protein antigen and four physicochemically distinct adjuvants.

Long-circulating, transfection-competent LNP-mRNA systems are key for effective extrahepatic delivery. Here, authors show that LNPs with high bilayer lipid ratios yield high mRNA encapsulation, prolonged circulation, and enhanced transfection in extrahepatic tissues.

Intracellular siRNA delivery is key for RNAi therapy. Here, the authors report on bioengineered nanovesicles with tumour cell-targeting and enzyme-activated membrane fusion functions for efficient cytosolic siRNA delivery to knockdown oncogenes, leading to effective tumour gene therapy.

Screening of DNA-encoded chemical libraries against prostatic acid phosphatase yielded OncoACP3, a modular small organic ligand with picomolar binding affinity that enabled targeted payload delivery to prostate cancer.

End-of-life nonhuman primates can be used to screen pools of lipid nanoparticles for clinical safety studies.

NICER is a broad-spectrum nanovaccine based on a nanovesicle system that can induce an effective immune response via epigenetic regulation to target both cancer stem-like cells and bulk tumour cells to prevent tumour recurrence.

Excessive fibrosis triggered by bisphosphonates impairs fracture healing in osteoporotic bone. Here, the authors develop an injectable magnesium-alendronate MOF-based hydrogel adhesive and show it prevents fibrosis and enhances bone repair, improving healing strength in an osteoporotic rat model.

Steroid resistant asthma can be combatted with antibody therapy, but delivery and off-target effects are a concern. Here, the authors report on the co-delivery of thymic stromal lymphopoietin nanobody mRNA and budesonide in budesonide-incorporated inhalable lipid nanoparticles to treat steroid resistant asthma.

Lipid nanoparticles (LNPs) delivering mRNA after intratumoral administration could be a promising cancer treatment strategy. Here this group reports the intratumoral delivery of mRNA with LNPs inducing the expression of purine nucleoside phosphorylase and inhibiting the progression of head and neck squamous cell carcinoma in vivo.

Modifying the polyethylene glycol lipid ratio and phospholipids in the lipid nanoparticle component of nucleoside-modified mRNA–lipid nanoparticle vaccines is shown to have an impact on the elicited cellular and humoral immune responses.

Effective delivery of therapeutic agents to the infection site and the modulation of the immunosuppressive microenvironment at the site of infection are vital for the treatment of chronic bacterial infections but remain elusive. Here, the authors address these issues by developing a nanomedicine that combines chemical and immunological therapies for chronic bacterial infection management.

Natural vesicles typically consist of a lipid membrane enclosing substances. Now a coacervate vesicle formed by liquid–liquid phase separation of cholesterol-modified DNA and histones has been developed. Unlike traditional vesicles, these lack a membrane and feature a high-density liquid layer around a water-filled cavity, offering enhanced kinetic stability and potential as a biopharmaceutical delivery system.

Han et al. report the design and characterization of a pressure-fused biomineral tablet for the long-acting sustained release of IL-2, promoting antitumor immune responses in preclinical models of melanoma.

Tumour endothelial cell macropinocytosis is the dominant mechanism for nanoparticle entry into the tumour. Enhanced nanoparticle tumour accumulation may be due to upregulated macropinocytosis membrane ruffling compared with most healthy tissues.

Chemotherapy is an important treatment for glioblastoma, but its effect is limited by the blood-brain barrier (BBB) and complex tumor microenvironment. Here, the authors address these issues by developing a Trojan horse-inspired nanobot system (Trojanbot) combining chemokine-guided neutrophil transport across the BBB with enzyme-driven nanobots that penetrate tumors via H₂O₂ gradients.

Stomata are key entry points for plant pathogens. Here, the authors engineer stomata-targeted nanoparticles to reduce bacterial colonization while preserving stomatal function, enabling a more precise strategy to enhance crop defence.

Exosomes have huge potential for drug delivery, but drug loading can be difficult. Here, the authors report on fusogenic lipid nanoparticles which, when mixed with exosomes rapidly fuse, non-destructively loading large drugs without compromising exosome biological functions, and demonstrate neurological application.

Microwave-assisted tumour-derived microparticles enhance antitumour activity, safety and drug delivery, outperforming traditional ultraviolet-derived methods.

Here, based on single-pass intestinal perfusion platform, the authors establish a microbiota-based drug permeability screening framework to compare perfusion and metabolomic profiles of 32 orally administered drugs in germ-free rats, and show that increased permeability of N-Acetylcysteine is mediated by cysteine-3-ketosphinganine of Bacteroides.

Cryoprotectants are needed for the storage of lipid nanoparticles (LNPs). Here, the authors report on a study which shows that freezing can be harnessed to reformulate LNPs in a way that both preserves their integrity and boosts mRNA delivery after sub-zero storage by increasing endosomal escape.

A collagenase nanogel backpack enhances CAR-T cell therapy in pancreatic cancer by improving cell infiltration and overcoming physical barriers, enabling potent tumour regression and prolonged survival.

Encapsulation of large-size DNA molecules into lipid nanoparticles (LNPs) remains challenging. Here, the authors engineer PEGylated LNPs with DNA and plasma proteins to improve the delivery of large DNA molecules, enhancing the gene therapy potential.

Reaching the depths of the respiratory tract is hard even with vapor-based drug delivery. Here, the authors devise inhalable biohybrid microrobots that, thanks to their motility, reach deeper regions of the lungs.

Engineered pyroptotic vesicles formed during tumour cell pyroptosis and engineered as personalized tumour vaccines can activate a robust antitumour immune response for post-surgical tumour recurrence inhibition.

This study identifies FABP4 as driver of postmenopausal osteoporosis and shows that targeting FABP4 with a small-molecule inhibitor or bone-targeted nanoparticles can reduce bone loss and offers a potential new treatment approach.

Genetic vaccines can be quickly formulated and tested but require multiple administrations to generate a durable antibody response, as in the case of protein subunit vaccines. Here SpyTag/SpyCatcher technology is used to develop a genetic vaccine encoding antigen-displaying capsid virus-like particles to enhance the immune response against the Pfs25 malaria antigen.