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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.

Cancer cell-derived small extracellular vesicles bind to therapeutic nanoparticles leading them from tumours to the liver for degradation. This mechanism is another barrier for the development of efficient nanoparticle-based cancer therapies.

A class of cationic—amidine-based degradable—lipids can now be readily synthesized through a tandem multi-component amine–thiol–acrylate conjugation reaction. Mechanistic studies provided key insights, from which the observed lead lipid enabled mRNA delivery to multiple organs, highlighting the potential for developing mRNA vaccines and therapeutics to treat various diseases.

mRNA delivery through LNPs targeting specific organs holds great clinical potential, but it remains unclear how the structure of the lipidoids in the LNPs controls organ tropism. Here the authors direct in vivo delivery of siloxane-based LNPs via structural alteration of the ionizable structure of the constituting lipidoids.

A subcutaneously injected hydrogel conjugated with antibodies for interleukin-6 substantially reduces the levels of the cytokine during chimaeric antigen receptor T-cell therapy while maintaining its antitumour efficacy.

Polyethylene glycol conjugation to chimeric antigen receptor T (CAR T) cells creates a physical block between CAR T cell interactions and other immune and tumour cells, controlling tumour lysis and immune response stimulation to mitigate cytokine release syndrome.

Gene delivery to fibroblasts for liver fibrosis treatment remains challenging. Here the authors develop a combinatorial library of ligand-tethered lipidoids via a modular synthetic method and adopt a 2-round screening strategy to identify lipidoids for potent and selective gene delivery to fibroblasts.

Immunological adjuvants are a crucial component of cancer vaccines. Here the authors design a light-activable immunological adjuvant, based on hypoxia-responsive amphiphilic dendrimer nanoparticles loaded with a photodynamic agent, promoting anti-tumor immune responses in preclinical cancer models.

By mimicking antigen processing and presentation during the rejection of xenotransplanted tissue, xenogeneic cell membrane-derived vesicles encapsulating peptide antigens or mRNA-encoded antigens function as vaccines targeted to dendritic cells.

Directed chemical evolution can iteratively accelerate the structural optimization of ionizable lipids to improve their delivery activity and biodegradability for applications in lipid nanoparticle-mediated mRNA delivery.

Lipid nanoparticles (LNPs) are the preeminent drug delivery vehicle for mRNA therapies, partially due to the ionizable lipid (IL) components that facilitate endosomal escape. Here, authors devise terminally branched ILs that enhance endosome escape, resulting in increased liver and T cell delivery.

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.

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.

A lipid nanoparticle (LNP) component—an adjuvant lipidoid—is developed to enhance the adjuvanticity of LNPs, which significantly increases the innate and adaptive responses of the COVID-19 mRNA vaccines with good tolerability in mice.

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.

A paper-based assay leveraging nucleic acid strand-displacement reactions and the enzymatic amplification of the recognition of viral RNA at the single-nucleotide level allows for the rapid colorimetric detection of SARS-CoV-2 variants.

A shape-changing pH-responsive cancer vaccine delivers antigenic peptides directly to the cytoplasm and boosts the cellular immune response upon activation of the inflammasome pathway, efficiently inhibiting tumour growth and extending survival in animal tumour models.

Antibiotic resistance is a major global health challenge. Here, the authors report on a thermoresponsive delivery system for combined photothermal and antibiotic delivery with fluorescent tracking abilities and demonstrate application against antibiotic resistant bacteria in vitro and in vivo.

Atomically dispersed gold supported by carbon dots amplifies mitochondrial oxidative stress, and leads to irreversible cell damage, inhibiting hepatocellular carcinoma in animal models.

Confining the Zika virus within a self-adjuvanting hydrogel that forms a subcutaneous inflammatory niche stimulates strong immune responses in mice without inducing infection.

A curvature-sensing peptide is used to disrupt exosomes for enhanced cancer immunotherapy.

Drug delivery to the bone marrow has limited efficiency, hitchhiking on bone marrow homing neutrophils offers a solution.

Lipid nanodiscs carrying a potent STING agonist penetrate deep into solid tumours compared with gold-standard liposomes and enable long-term antitumour immunotherapy.

In situ cancer vaccines generate tumour-specific T cell responses and hold promise for the treatment of solid tumours. This Review discusses drug delivery technologies such as lipid nanoparticles, hydrogels and scaffolds that are being developed to boost the antitumour immune effects of several types of in situ cancer vaccine.

Immunotherapy represents an important advance in cancer treatment, yet faces challenges owing to lack of precise control, leading to systemic effects and suboptimal results for patients. This Review explores how responsive biomaterials can enhance cancer immunotherapies by responding to various internal and external stimuli to regulate the delivery and behaviour of therapeutic agents, thereby improving efficacy and reducing toxicity in treatment methods such as cancer vaccines, T cell-based therapies and sustained delivery systems.

This Review discusses the progress and the remaining challenges for the clinical application of nanomaterial-based T-cell immunotherapies.