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Biobased materials are of interest for many applications. Here the authors report insect-derived peptides that self-assemble into hollow nanocapsules through a gradient-driven, single-step, solvent exchange process, enabling the encapsulation of diverse cargoes with potential for drug delivery applications.

Challenges including hypoxia, inflammation, and inadequate exosome intracellular delivery hinder wound healing. Here, the authors show that a multifunctional exosome-coated oxygen nanobubble-laden hydrogel enhances exosome delivery and mitigates hypoxia for enhanced wound healing.

Antimicrobial resistance is becoming more prevalent. Here the authors use multimodal nanoparticles to modulate the infected microenvironment, recruit neutrophils and alleviate hypoxia to restore neutrophil function, demonstrating therapeutic efficacy against MRSA infections in mice.

Branched ionizable lipids have aroused great interest for mRNA delivery. Here, the authors devise an in situ construction method for combinatorial synthesis of degradable branched ionizable lipids and summarize key design criteria to enable potent delivery of mRNA therapeutics and gene editors.

The densities of blood vessels and of tumour-associated macrophages are key predictive features of the degree of accumulation of polymeric and liposomal nanomedicines, as shown for specimens of mouse and human tumours.

Prodrugs have the potential for improving therapeutic index and expanding drug targets, but current prodrug activation strategies that are responsive to endogenous stimuli can result in unintended drug release and systemic toxicity. Here, the authors report 3-vinyl−6-oxymethyltetrazine (voTz) as an all-in-one reagent for modular preparation of tetrazine-caged prodrugs and chemoselective labeling of peptides to produce bioorthogonal activable peptide-prodrug conjugates.

Photoinduced electron transfer (PET) occurs in many chemical processes and has various applications. Here ionizing radiation was used to trigger PET for controlled drug release from an antibody–drug conjugate using a picolinium cage. The radiotherapy-activated prodrug system demonstrated high antitumour efficacy and minimal side effects.

In non-small cell lung cancer (NSCLC), inactivating p53 mutations can drive resistance to cisplatin. Here, the authors develop fluplatin nanoparticles comprising a prodrug of cisplatin and fluvastin (mutant p53 inhibitor) which selectively degrades mutant p53, prevent tumor recurrences in preclinical models of p53 mutant NSCLC.

Insects have been shown to have the ability to detect different chemical agents. Here, the authors present a nanomaterial-assisted neuromodulation strategy to augment the chemosensory abilities of insects via photothermal effect and on-demand neurotransmitter release from cargo-loaded nanovehicles to augment natural sensory function.

The esterification of butyrate to serine makes for an odourless and tasteless oral prodrug that ameliorated disease severity and reduced inflammatory responses in mouse models of rheumatoid arthritis and multiple sclerosis.

CXCR4-targeted therapies have been proposed for the treatment of cancer metastasis. Here the authors propose a CXCR4-targeted strategy based on interactable polymer nanothreads, showing inhibition of metastasis in preclinical cancer models.

The development of prodrugs — derivatives of active pharmaceutical ingredients (APIs) with little or no biological activity themselves that are converted into the API after administration — can address issues with properties of the API such as poor bioavailability. This article provides a holistic analysis of approved prodrugs and discusses trends in prodrug design, their indications, mechanisms of API release and the chemistry of promoieties added to APIs to form prodrugs.

Understanding how cells process nanoparticles is crucial to improve nanomedicine efficacy. Here a genome-wide screening is used to discover proteins that are involved in silica nanoparticle accumulation by cells and shows that different apolipoprotein receptors and proteoglycans mediate their internalization.

Tumour cell behaviour is an underdeveloped target for cancer intervention. Here the authors report on a spatiotemporal interaction between tumour cells and osteoclasts in initial bone metastases and propose a behaviour-targeting therapy with an in situ physical killing strategy.

Achieving targeted drug delivery for calcified aortic valve is challenging. Here, the authors find that protease activated receptor 2 (PAR2) is up-regulated on calcified valves and develop a magnetic nanocarrier functionalized with PAR2-targeting peptide for dual-active drug delivery.

Insulin injections are not ideal and have an increased risk of hypoglycaemia. A preferable oral formulation based on silver sulfide quantum dots coated with a chitosan/glucose polymer is discussed, which has controlled insulin release and reduced risk of hypoglycaemia, and demonstrates applications in rodent and non-human primate models.

The treatment of hypertrophic scar (HS) is hindered by the low bioavailability of drugs and the pathological microenvironment. Here the authors report a separating microneedle drug delivery system responsive to high reactive oxygen species levels and overexpression of matrix metalloproteinases to remodel the pathological microenvironment for HS treatment.

The spacing of ligands presented to cells can have a huge impact on cellular responses. DNA origami is used to block structures to control the distribution of Toll-like receptor ligands and optimize presentation in the activation of dendritic cells in cancer immunotherapy.

The intravenous injection of neutrophils bearing discoidal polymer microscale ‘patches’ on their surfaces reduces tumour burden in mice owing to the patch-induced polarization of the neutrophils towards an antitumour phenotype.

Treatment of the chronic disease ulcerative colitis is impeded by systemic side effects of orally administered drugs. Here the authors develop a gel that uses the rectal temperature as a mechanism to trigger solidification for localized delivery of colitis therapeutics.

Sequential drinks of crosslinker and polymer solutions form a tough hydrogel in the stomach, enabling delivery of drugs and biologics in this harsh chemical environment.

Identifying pulmonary delivery of lipid libraries poses an obstacle for mRNA drugs. Here, the authors use a barcoded screening system to identify lung-targeting of cationic, degradable lipid-like materials for mRNA delivery and gene editing in female preclinical models.

The delivery of CRISPR RNPs has potential advantages over other genome editing approaches, including reduced off-target editing and reduced immunogenicity. Here the authors report self-deliverable Cas9 RNPs capable of robustly editing cultured cells in vitro and the mouse brain upon direct injections.

Using nanoparticles featuring anisotropic characteristics is a promising approach to developing multifunctional platforms for drug delivery and theranostics. This Review discusses methods to generate anisotropy in nanosystems and strategies to control particle transport, targeting and interaction with cells to overcome biological barriers.

Polymers are promising for mRNA delivery, but can have limited efficacy in hard to transfect cells. Here, the authors report charge-altering releasable transporters for improved mRNA transfection in primary T-lymphocytes and enhanced and selective protein expression in vivo.

Cholesterol (Chol) transfer from lipid bilayer jeopardizes membrane stability and causes premature payload leakage, yielding suboptimal efficacy. Here, the authors report a Chol-modified sphingomyelin (SM) bilayer via covalently conjugating Chol to SM, which retains Chol condensing ability and improves pharmacokinetics and therapeutic delivery of various drugs in diverse disease animal models.

Tuberculosis is a major global health issue. Here the authors report Mycobacterium-pre-activated macrophage membrane-coated photothermal nanoparticles for targeted tuberculous granuloma and pathogen dual imaging and antibacterial photothermal therapy.

Manufacturing complexities, low yield and stability issues have hampered the clinical translation and scaling-up of immunoliposomes to meet the needs of pharmaceutical-grade products. The authors propose a one-step method of incorporating chimeric nanobodies tagged to hydrophobic linkers into liposomes, allowing targeted delivery of small-molecule anti-cancer drugs to tumours.

In regenerative medicine, stem-cell-derived extracellular vesicles are emerging as cell-free nanotherapeutics. Here, the authors show that coating these nanovesicles with blood proteins such as albumin improves their uptake by liver cells, offering a better treatment strategy for liver diseases.

Triggering the PD-1/PD-L1 immune checkpoint is an attractive therapeutic approach in inflammatory bowel disease, and PD-L1, conjugated to the Fc part of an immunoglobulin (PD-L1-Fc) has been shown to be effective in mouse models. Here authors show that fusing to reactive oxygen species (ROS)-responsive nanoparticles improves effect of PD-L1-Fc due to targeting to inflammation sites, while systemic toxicity is reduced.

The off-tumour toxicity of a supramolecular bispecific T cell engager can be halted by disengaging T cells from the tumour cells via the disassembly of the supramolecular aggregate through the infusion of the small-molecule drug amantadine.

Limited tumor cell delivery is a major challenge for the efficacious delivery of siRNAs to silence traditionally undruggable oncogenes. Here the authors optimize siRNAs for in situ binding to albumin through C18 lipid modifications and show the application of the lead conjugate structure for targeting MCL1 in orthotopic breast tumors in mice.

Immune checkpoint blockade-based immunotherapy has shown limited efficacy in patients with glioblastoma (GBM). Here the authors describe the design of redox-responsive micelles for increasing the delivery of paclitaxel and anti-PD-L1 in the brain, showing improved anti-tumor immune response in preclinical GBM models.

The dynamic protein corona hinders the uptake of nanocarriers in desired target cell populations, limiting their bench-to-bedside translation. Here the authors reveal that the modification of hydroxyl and amino functional groups on nanovesicles can rationally regulate the composition of protein coronas to improve the efficiency of targeted drug delivery.

Protecting the whole small intestine from radiation-induced intestinal injury during the radiotherapy of abdominal or pelvic solid tumors remains an unmet clinical need. Here the authors use a natural microalga to readily construct an oral delivery system to achieve effective radioprotection for the small intestine.

Different approaches have been described for the transdermal delivery of drugs. Here the authors report the design of a fluorocarbon modified chitosan-based non-invasive transdermal platform for the delivery of biomacromolecules, such as viral antigens for vaccines or immune checkpoint inhibitors for melanoma immunotherapy.

The mechanical dysregulation of cells is associated with several diseases and strategies to deliver drugs based on the “mechanical phenotype” of a cell are desirable. Here, the authors design and characterize DNA mechanocapsules comprised of DNA tetrahedrons that are force responsive, and showed they can encapsulate macromolecular cargo and release it upon application of force.

Local anesthetic sustained release systems suffer from untriggered rapid drug release upon application. Here the authors overcome this issue by covalently linking tetracaine to a polymer gel via a photo-cleavable linkage, enabling light-triggered and repeatable drug release.

Effective reprogramming of chronic wound healing remains challenging due to the limited drug delivery efficacy hindered by physiological barriers, as well as the inappropriate dosing timing in distinct healing stages. Here, the authors report a core-shell structured microneedle array patch with programmed functions which dynamically modulates the wound immune microenvironment according to the varied healing phases

Functionalization of C-H bonds typically requires harsh reagents or metal catalysts. Here the authors report a metal-free C-H sulfenylation/rearrangement to form C-S and S=N bonds under simple, biocompatible conditions, and apply this to the synthesis of fluorogenic phospholipid vesicles.

Long-term control of therapeutic transgene expression is needed. Here the authors report a muscone-induced transgene system packaged into AAVs based on a G protein-coupled murine olfactory receptor and a synthetic cAMP-responsive promoter: they show dose- and exposure-time-dependent gene expression control in mice.

In this work, the authors report the use of a computationally and rationally designed self-assembling peptide that has robust antiviral capability with demonstrated specificity in binding to SARS-CoV-2 and inhibition of viral entry into human cells.

Proteins absorbed on nanomaterials often lose function due to denaturation. A poly(propylene sulfone) nanoparticle with site-specific dipole relaxation has been reported, which allows proteins to anchor to the nanoparticle without disrupting the hydrogen bonding or structure maintaining the protein functionality.

Autologous skin flap transplantation is a common method to repair complex soft tissue defects. Here the authors develop a hydrogel patch that releases carbon monoxide and nitric oxide gases on demand, to afford a timely blood supply for skin flap transplantation during surgery, just improving the incidence of distal necrosis of the flap and reducing long-term functional loss.

Protein degradation is a powerful tool for a range of applications and therapies. Here, a selective autophagy receptor mimetic against mutant p53 protein is developed to substantially elevate autophagy levels and to recognize and transport mutant proteins for autophagy-mediated degradation and anticancer effect.

Small interfering RNA is degraded by plasma and can’t cross the cell membrane due to its negative charge. Here, the authors present an influenza inspired polymer carrier, capable of local RNA delivery, which degrades to a non-toxic by-product, and is thus suitable for multiple doses.

Intratumoral abundance of chemokines, such as CXCL9, is an important driver of T cell infiltration in tumors. Here the authors describe the design of a tumor-specific expression strategy to drive secretion of CXCL9 and an anti-PD-L1 scFv (αPD-L1) in the tumor microenvironment, promoting T cell recruitment and anti-tumor immune response in preclinical cancer models.

Cytokine interleukin-12 (IL-12) has potential for tumour suppression yet off-target effects limit potential applications. Here the authors report on the delivery of IL-12 mRNA encapsulated in extracellular vesicles to lungs via inhalation and demonstrate the immunotherapeutic potential of targeted cytokine mRNA therapy.