Delivery of drugs and biologics

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.

The delivery of mRNAs into neurons at inflammatory sites in vivo can be enhanced by engineering leucocytes to produce extracellular vesicles incorporating mRNA-packaging retrovirus-like capsids.

The targeted integration of large DNA payloads into primary human T cells can be efficiently achieved non-virally by leveraging Cas9-based editing and the DNA-repair pathway homology-mediated end joining.

The composition of lipid nanoparticles for the delivery of tumour-antigen-encoding mRNA can be optimized via a screening method to enhance antitumour activity via the modulation of the immune activity of helper T cells.

The immunization of mice with colitis with self-assembling supramolecular peptide nanofibres bearing phosphorylcholine epitopes induced sustained levels of anti-phosphorylcholine antibodies that were both protective and therapeutic.

A subcutaneous injection of a glucose-responsive formulation of insulin that does not trigger the formation of a fibrous capsule leads to week-long normoglycaemia in mice and minipigs with type 1 diabetes.

Adjuvanting the lipid and the encapsulated messenger RNA-encoded antigen in lipid-nanoparticle mRNA vaccines can enhance the efficiency of mRNA delivery and the activation of the immune responses, as shown for a COVID-19 vaccine in mice.

A high-throughput method leveraging peptide-encoding mRNA barcodes for the in vivo screening of libraries of nanoparticle formulations allows for the rapid optimization of a lipid nanoparticle for the delivery of mRNA to the liver.

Extracellular vesicles encapsulating mRNA encoding for extracellular-matrix collagen and delivered intradermally via microneedles led to the replacement of collagen in the dermis of mice with photoaged skin.

Radionuclide brachytherapy delivered via an injectable biopolymer depot conjugated with iodine-131 and combined with systemically delivered paclitaxel induced the complete regression of multiple subcutaneous and orthotopic pancreatic tumours in mice.

The encapsulation of antibiotics in glucosylated polymeric nanoparticles that are readily absorbed by the proximal small intestine improves the bioavailability of the antibiotics and limits their exposure to flora in the large intestine.

Lipid nanoparticles can be optimized for the efficient delivery of therapeutic mRNAs to the lung via nebulization, as shown for the delivery of a therapeutic antibody in mice challenged with a lethal dose of the H1N1 influenza A virus.

Orally delivered nanocarriers of insulin or rapamycin made from a polymeric bile acid exert metabolic and immunomodulatory functions, restore blood-glucose levels in mice and pigs with type 1 diabetes, and delay the onset of diabetes in mice.

The loading of two different protein therapeutics onto extracellular vesicles can be optimized by genetically engineering the parent cells, as shown for extracellular vesicles displaying decoy receptors for two pro-inflammatory cytokines.

A self-assembling supramolecular delivery system for site-1 sodium channel blockers designed to mimic specific interactions on voltage-gated sodium channels led to prolonged nerve blockade and to reduced systemic toxicity in rats.

An intra-articularly injected depot of nanoparticles targeting collagen and delivering small interfering RNA for matrix metalloproteinase 13 protects cartilage integrity and joint structure in mice with post-traumatic osteoarthritis.

Intravitreally injected exosomes derived from regulatory T cells and conjugated with an antibody for vascular endothelial growth factor via a cleavable linker markedly suppress ocular neovascularization in mice and non-human primates.

Nanoparticles releasing an oxaliplatin prodrug and a cationic DNA intercalator within temozolomide-resistant gliomas in mice after convection-enhanced delivery inhibit the growth of the tumours without causing any detectable toxicity.

Cryogenic microneedle patches can deliver mammalian cells before dissolving into the skin, as shown with the transdermal delivery of ovalbumin-pulsed dendritic cells in mice with subcutaneous tumours.

A hydrogel implanted into the cavity of a resected tumour and releasing CAR-T cells and platelets conjugated with a checkpoint inhibitor inhibits local tumour recurrence and the growth of distant tumours in mice.

Conjugates of small-molecule anticancer drugs with a polyzwitterion that has negligible interaction with proteins and a weak interaction with phospholipids eradicate large tumours and patient-derived tumour xenografts in mice.

Exosome-eluting stents implanted in rats after ischaemic injury accelerate vascular healing and promote tissue regeneration.

This Review Article discusses how delivery challenges associated with small molecules, nucleic acids, peptides, proteins and cells led to the development of commercial products and are now informing the delivery of live-cell therapeutics.

Patches of transdermal core–shell microneedles, fabricated via additive manufacturing of polymer shells with varying degradability kinetics, enable the preprogrammed burst release of vaccine payloads over a period of a few days to more than a month.

The systemic administration of erythrocytes with chemokine-encapsulating nanoparticles non-covalently anchored to their surface results in local and systemic tumour suppression in mouse models of lung metastasis.

The magnetically induced accumulation and release of circulating exosomes into infarcted heart tissue from antibody-conjugated magnetic nanoparticles improves angiogenesis and heart function in rat and rabbit models of myocardial infarction.

The enhanced accumulation and residence time of systemically administered interleukin-4 fused to serum albumin in lymph nodes and in the spleen prevents the development of multiple sclerosis in mice.

The sustained release of a leukaemia-associated epitope peptide and of anti-PD-1 antibody co-encapsulated in degradable microcapsules results in superior therapeutic outcomes in mouse models of leukaemia.

Systemically injected lipid–polymer nanoparticles encapsulating small interfering RNA for silencing genes in bone-marrow endothelial cells of mice improved the healing of the mice after myocardial infarction.

A gelling hypotonic solution for ocular delivery that forms a uniform and clear thin layer conformal to the ocular surface resists clearance from blinking and extends the residence time of the delivered drugs.

The burst release of annexin A5 from intravenously injected nanoparticles that rapidly degrade in tumours generates robust anti-tumour immunity by shifting late-stage immunosuppressive apoptosis to immunostimulatory necrosis.

Intratumoural injection of a self-assembling supramolecular hydrogel that slowly releases a STING agonist and a chemotherapeutic agent reduces tumour immunosuppression and increases antitumour responses in mice.

Methotrexate-loaded tumour-cell-derived microvesicles induce neutrophil-mediated antitumour activity and can relieve biliary obstructions in patients with extrahepatic cholangiocarcinoma.

An orally delivered encapsulated bacterial cocktail that metabolizes blood nitrogenous waste products in the gut reduces urea and creatinine concentrations in the blood of animal models of acute and chronic kidney injury.

Inducing a slight and transient depletion of erythrocytes in mice via the administration of a low dose of allogeneic anti-erythrocyte antibodies increases the circulation half-life of nanoparticle formulations.

The combination of tumour-infarction therapy and chemotherapy, delivered via nanoparticles decorated with a tumour-homing peptide and encapsulating thrombin and doxorubicin, outperforms the corresponding monotherapies in tumour-bearing mice and rabbits.

A single removable transdermal patch bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix regulates blood glucose in insulin-deficient diabetic mice and minipigs.

A macroporous material encapsulating an immune-cell-activating cytokine, an adjuvant and tumour-associated antigens elicits prophylactic immunity to acute myeloid leukaemia in mice, and eradicates the disease when combined with chemotherapy.

Integrating silencing RNA into the backbone of a microRNA that is highly enriched in small extracellular vesicles reduces the therapeutic dose of the silencing RNA.

A cellular-nanoporation method produces large quantities of exosomes containing therapeutic mRNAs and targeting peptides that restore tumour-suppressor function in mice with orthotopically implanted phosphatase and tensin homologue (PTEN)-deficient brain gliomas.

Micropatterned nitinol (a nickel titanium alloy) thin films loaded with human CAR-T cells and implanted into tumours foster the expansion of the cells and extend animal survival in mouse models of human tumours.

The local delivery of a calcium channel blocker and a Rho-kinase inhibitor, determined by screening for small molecules that cause ureteral relaxation, significantly reduce ureteral contraction in pigs.

Anionic nanoparticles increase intestinal permeability and enable the oral delivery of proteins, as shown with the delivery of insulin in healthy, hyperglycaemic, and diabetic mice.

The polymer encapsulation of the monoclonal antibody rituximab and the ligand-mediated targeting of metastases in the central nervous system significantly improve antitumour efficacy in mouse models of metastatic non-Hodgkin lymphoma.

Dextran nanoparticles loaded with a chemotherapeutic agent and bound to phages that eliminate a pro-tumoural gut bacterium and promote the growth of anticancer-compound-producing bacteria boost chemotherapy responses in mouse models of colorectal cancer.

The efficiency of delivery of anticancer drugs by microparticles derived from tumour-repopulating cells isolated from 3D fibrin gels is enhanced by the microparticles’ softness.

A mechanical injector that targets tissue by sensing the loss-of-resistance on encountering softer tissue or a cavity can reliably and precisely deliver liquids to the suprachoroidal space, and to other injection-accessible target sites in the body.

A microneedle skin patch with rapidly separable, biodegradable polymer needles continuously releases the contraceptive levonorgestrel for over one month in rats.

DNA origami nanostructures with different shapes can accumulate preferentially in the kidney, with some being renal-protective, as shown in healthy mice and in a mouse model of acute kidney injury.

The systemic administration of haematopoietic stem cells conjugated to anti-PD-1-decorated platelets in leukaemic mice promotes the delivery of the checkpoint inhibitor to the bone marrow and suppresses the growth and recurrence of leukaemia.

The reintroduction of PTEN mRNA into PTEN-null prostate cancer cells via encapsulation in polymer–lipid nanoparticles delivered systemically leads to significant inhibition of tumour growth in mouse models of prostate cancer.

Macromolecular telmisartan prodrugs optimized for preferential release in fibrotic liver tissue reduce liver fibrosis in mouse models, and are retained and well tolerated in the liver tissue of rats and dogs.

Polymer microparticles loaded with lytic bacteriophages that deposit throughout the lung via dry powder inhalation rescue mice from pneumonia-associated death.

Gene editing of a single gene in the brain of an adult mouse model of fragile X syndrome, achieved via the intracranial injection of a nonviral Cas9 delivery vehicle, rescues mice from the exaggerated repetitive behaviours caused by the disease.

β-Cyclodextrin nanoparticles carrying an antagonist of the toll-like receptors TLR7 and TLR8 drive the M1 phenotype in tumour-associated macrophages and improve immunotherapy response rates in tumour mouse models when used with checkpoint blockade.

Polymer–lipid micelles with an ultralow undetectable critical micelle concentration make ultrastable drug carriers that significantly enhance therapeutic outcomes in a mouse model of melanoma.

The modification of protein and peptide therapeutics with tannic acid improves their ability to specifically target heart tissue, as shown with a rat model of myocardial ischaemia-reperfusion injury.

A hydrogel patch for the sustained delivery of extracellular vesicles from cardiomyocytes derived from induced pluripotent stem cells improves tissue regeneration in infarcted rat hearts.

A nanoparticle-based immunotherapy targeted to a protein responsible for signalling between monocytes and macrophages reduces plaque inflammation in atherosclerotic mice and appears to be safe in non-human primates.

Topically applied imaging nanoprobes for the detection of intracellular mRNA expression from connective tissue growth factor enable the detection of hypertrophic scars and keloids in the skin of small live animals and in ex vivo human skin.

Nanoparticles carrying an antibiotic and conjugated with a peptide identified via phage display that binds specifically to Staphylococcus aureus effectively suppress staphylococcal infections in vivo.

The slow release of pro-survival peptide analogues crosslinked to an injectable collagen–dendrimer biomaterial significantly prolongs the engraftment and survival of transplanted stem cells in mouse models of ischaemic injury.

The attachment of platelet nanovesicles to the surface of cardiac stem cells increases the retention of the cells delivered to the heart and reduces infarct size in rat and pig models of acute myocardial infarction.

An injectable hyaluronic acid hydrogel for the sustained delivery of miR-302 mimics to the heart promotes cardiomyocyte proliferation and improves cardiac function in mice after myocardial infarction.

Gold nanoparticles carrying Cas9 ribonucleoprotein and donor DNA, and complexed with endosomal disruptive polymers, correct the DNA mutation that causes Duchenne muscular dystrophy in mice, with minimal off-target effects.

A dendrimer that depletes bioavailable copper and leads to the suppression of tumour angiogenesis acts as a potent and non-cytotoxic anticancer therapeutic.

Ultrasound pulses controlling the release of an anaesthetic encapsulated in liposomes allow for the timing, intensity and duration of sciatic-nerve blocks in rats.

Polymer–lipid–peptide nanoparticles carrying an antiplatelet antibody and a chemotherapy drug deplete tumour-associated platelets to increase vascular permeability and augment the accumulation of the drug in tumours.

In a rabbit model of prosthetic joint infection, optimization of the shape and loading of antibiotic clusters in a polymer implant augments and prolongs antibiotic elution while maintaining implant strength and wear rate.

Rapid DNA expression in millions of cells per minute can be achieved with a microfluidic device that integrates mechanical squeezing of the cells and electric-field-mediated transient disruption of the plasma and nuclear membranes.

Drawing from recent successes in cancer immunotherapy, this Perspective discusses that effective cancer-nanomedicine therapies can be designed to prime antitumour immunity far from the site of disease.

By targeting the surgical bed and circulating tumour cells, platelets conjugated with an antibody against an immune checkpoint protein prevent tumour recurrence and metastasis following resection of the primary tumour.

Conjugation of exendin-4 — a drug to treat type 2 diabetes — with a poly(ethylene glycol) (PEG)-based brush polymer reduces the conjugate's reactivity towards anti-PEG antibodies and leads to lower blood glucose levels in mice for up to 5 days after a single injection.

The newest strategies for delivering therapeutics to specific cells and tissues are increasingly translationally promising.

Lipid nanoparticles can be optimized for the efficient delivery of mRNA via nebulization.

The partial depletion of red blood cells via the administration of a low dose of anti-erythrocyte antibodies increases the circulation half-life of nanomedicines, as shown in rodent models of cancer.

Locally delivering therapeutic T cells into solid tumours in mice via thin nitinol films loaded with the cells lengthens the animals’ survival.

The therapeutic dose of small interfering RNA can be reduced by endogenously expressing and packaging the RNA into extracellular vesicles through its integration with the backbone of a highly enriched pre-microRNA.

Negatively charged nanoparticles of about 50 nm in size permit the oral delivery of insulin and other peptide drugs by temporally enhancing the permeability of the intestinal wall.

An injectable biomaterial vaccine encapsulating antigens associated with acute myeloid leukaemia, dendritic-cell-targeting pro-inflammatory cytokines and an adjuvant protects mice from the disease.

Large quantities of extracellular vesicles produced via cellular nanoporation, and loaded with endogenously transcribed therapeutic mRNAs and targeting peptides, boost therapeutic outcomes in vivo.

Translational cancer nanomedicine needs to increasingly exploit newly discovered tumour-targeting strategies as well as the further optimization of proven means to selectively increase the concentration of cytotoxic drugs in solid tumours.

Encapsulation of the therapeutic monoclonal antibody rituximab, and its molecular targeting to brain metastases of B-cell lymphoma, significantly boosts the antibody’s therapeutic effectiveness in mice.

Drug-loaded nanoparticles that specifically bind to phages infecting cancer-promoting bacteria found in colonic tumours augment the effects of chemotherapy against colorectal cancer in mice.

A patch that deposits an array of microneedle tips under the top layer of the skin enables weeks-long delivery of a contraceptive in rats.

Widespread editing of the mutated DMD gene by CRISPR–Cas9, systemically delivered via an adeno-associated virus, restores dystrophin expression in a canine model of Duchenne muscular dystrophy.

The coupling of blood platelets bearing anti-programmed cell death protein 1 antibodies to haematopoietic stem cells enables delivery of checkpoint-blockade therapy to bone marrow to promote T-cell-mediated control of leukaemia in mice.

Two drug-loaded nanoparticle formulations that preferentially accumulate within tumour-associated macrophages induce macrophage repolarization to a tumoricidal state that leads to potent antitumour activity in multiple murine models of cancer.

Polymer-coated gold nanoparticles carrying the CRISPR components for knocking out, in the striatum of adult mice with fragile X syndrome, a gene implied in the syndrome’s pathophysiology rescue the mice from the exaggerated repetitive behaviours characteristic of the syndrome’s phenotype.

When designing translationally relevant delivery strategies to overcome the physicochemical and biological barriers to getting therapeutics into the right tissues and cells, building on tried-and-tested concepts often pays off.

Lipoprotein nanoparticles delivering an inflammation-targeting signalling inhibitor reduce vascular inflammation in atherosclerotic mice.

Self-assembled weakly negative nanoparticles bearing an octet of short interfering RNAs, targeting ligands and endosomolytic peptides lead to efficient gene silencing in a mouse model of prostate cancer.

The sustained delivery of extracellular vesicles, secreted by induced-pluripotent-stem-cell-derived cardiomyocytes, through a hydrogel patch promotes cardiac recovery after myocardial infarction in rats.

Micelles of a superhydrophilic zwitterionic polymer covalently linked to a superhydrophobic lipid remain stable at extremely dilute conditions and enhance the delivery of hydrophobic chemotherapeutics in vivo.

Topically applied spherical nucleic acids targeting an intracellular mRNA biomarker associated with abnormal scarring enable the fluorescent detection of abnormal scars during wound healing.

Nanoparticles carrying an antibiotic and bearing a peptide that targets the bacterium Staphylococcus aureus effectively suppress staphylococcal infections in mice.

Grafting platelet-derived nanovesicles onto the surface of cardiosphere-derived cardiac stem cells enables the cells to better engraft in infarcted tissue following systemic injection in rats and pigs.

Prolonged local delivery, via an injectable hydrogel, of a miRNA known to induce cardiomyocyte proliferation stimulates the recovery of mice from myocardial infarction.

The DNA mutation that causes Duchenne muscular dystrophy in mice can be corrected, with minimal off-target effects, by gold nanoparticles carrying the CRISPR components.

A dendrimer that depletes bioavailable copper as a result of its internal make-up displays powerful anticancer activity in mice, and no observable adverse effects.

Depletion of tumour-associated platelets improves the delivery of anticancer drugs.

The ability to release an anaesthetic from liposomes by applying ultrasound opens up the possibility of managing localized pain on-demand.

Exosomes expressing CD47 and loaded with interfering RNA dodge phagocytosis and accumulate in pancreatic tumours to silence the expression of the oncogene Kras in mice, with remarkable therapeutic efficacy.

A subcutaneous depot of a diabetes drug fused to a thermosensitive biopolymer leads to blood-glucose control, for over one week after a single injection, in animal models of type-2 diabetes.

An optimized drug-eluting polymer for the surface of articulating artificial joints may make them infection-free.

A microfluidic device that integrates mechanical squeezing and electrical stimulation delivers DNA to the nucleus of cells at a rate of millions of cells per minute.

Platelets delivering the immunotherapeutic antibody anti-PD-L1 to the site of surgically removed tumours reduce cancer recurrence and metastatic spread in mice.

Conjugation of a diabetes drug with a brush polymer reduces the reactivity of the drug conjugate towards pre-existing polymer antibodies in human plasma and improves the drug's performance in diabetic mice.