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Biomacromolecules are highly promising therapeutic modalities to treat various diseases. However, they suffer from poor cellular membrane permeability, limiting their access to intracellular targets. Strategies to overcome this challenge often employ nanoscale carriers that can get trapped in endosomal compartments. Here we report conjugated peptides that form pH- and redox-responsive coacervate microdroplets by liquid–liquid phase separation that readily cross the cell membrane. A wide range of macromolecules can be quickly recruited within the microdroplets, including small peptides, enzymes as large as 430 kDa and messenger RNAs (mRNAs). The therapeutic-loaded coacervates bypass classical endocytic pathways to enter the cytosol, where they undergo glutathione-mediated release of payload, the bioactivity of which is retained in the cell, while mRNAs exhibit a high transfection efficiency. These peptide coacervates represent a promising platform for the intracellular delivery of a large palette of macromolecular therapeutics that have potential for treating various pathologies (for example, cancers and metabolic diseases) or as carriers for mRNA-based vaccines. Coacervate microdroplets formed from pH- and redox-responsive peptides and self-assembled by liquid–liquid phase separation have been shown to quickly recruit macromolecular therapeutics—such as peptides, large proteins and mRNAs—and directly enter the cytosol of cells via a non-endocytic pathway. The subsequent release of therapeutic cargo is mediated by endogenic glutathione.

Nanomedicine-based anti-neuroinflammation strategy has become a promising dawn of Parkinson’s disease (PD) treatment. However, there are significant gaps in our understanding of the therapeutic mechanisms of antioxidant nanomedicines concerning the pathways traversing the blood-brain barrier (BBB) and subsequent inflammation mitigation. Here, we report nanozyme-integrated metal-organic frameworks with excellent antioxidant activity and chiral-dependent BBB transendocytosis as anti-neuroinflammatory agents for the treatment of PD. These chiral nanozymes are synthesized by embedding ultra-small platinum nanozymes (Ptzymes) into L-chiral and D-chiral imidazolate zeolite frameworks (Ptzyme@L-ZIF and Ptzyme@D-ZIF). Compared to Ptzyme@L-ZIF, Ptzyme@D-ZIF shows higher accumulation in the brains of male PD mouse models due to longer plasma residence time and more pathways to traverse BBB, including clathrin-mediated and caveolae-mediated endocytosis. These factors contribute to the superior therapeutic efficacy of Ptzyme@D-ZIF in reducing behavioral disorders and pathological changes. Bioinformatics and biochemical analyses suggest that Ptzyme@D-ZIF inhibits neuroinflammation-induced apoptosis and ferroptosis in damaged neurons. The research uncovers the biodistribution, metabolic variances, and therapeutic outcomes of nanozymes-integrated chiral ZIF platforms, providing possibilities for devising anti-PD drugs. The treatment of Parkinson’s disease (PD) is hampered by the lack of effective blood–brain barrier (BBB) traversing drugs. Here, the authors report nanozyme-integrated metal-organic frameworks with antioxidant activity and chiral-dependent BBB transendocytosis as anti-neuroinflammatory agents for PD treatment.

Multidrug-resistant (MDR) bacteria cause severe clinical infections and a high mortality rate of over 40% in patients with immunodeficiencies. Therefore, more effective, broad-spectrum, and accurate treatment for severe cases of infection is urgently needed. Here, we present an adoptive transfer of macrophages loaded with a near-infrared photosensitizer ( Lyso700D ) in lysosomes to boost innate immunity and capture and eliminate bacteria through a photodynamic effect. In this design, the macrophages can track and capture bacteria into the lysosomes through innate immunity, thereby delivering the photosensitizer to the bacteria within a single lysosome, maximizing the photodynamic effect and minimizing the side effects. Our results demonstrate that this therapeutic strategy eliminated MDR Staphylococcus aureus (MRSA) and Acinetobacter baumannii (AB) efficiently and cured infected mice in both two models with 100% survival compared to 10% in the control groups. Promisingly, in a rat model of central nervous system bacterial infection, we performed the therapy using bone marrow-divided macrophages and implanted glass fiber to conduct light irradiation through the lumbar cistern. 100% of infected rats survived while none of the control group survived. Our work proposes an efaficient and safe strategy to cure MDR bacterial infections, which may benefit the future clinical treatment of infection. There is increased demand for effective, broad-spectrum treatment options against severe, multi-drug resistant bacterial infections. Here, Wang et al describe an effective photodynamic therapy based on the adoptive transfer of macrophages loaded with a lysosomal photosensitiser.

Despite bacterial-mediated biotherapies have been widely explored for treating different types of cancer, their implementation has been restricted by low treatment efficacy, due largely to the absence of tumor-specific accumulation following administration. Here, the conjugation of aptamers to bacterial surface is described by a simple and cytocompatible amidation procedure, which can significantly promote the localization of bacteria in tumor site after systemic administration. The surface density of aptamers can be easily adjusted by varying feed ratio and the conjugation is able to increase the stability of anchored aptamers. Optimal bacteria conjugated with an average of 2.8 × 10 5 aptamers per cell present the highest specificity to tumor cells in vitro, separately generating near 2- and 4-times higher accumulation in tumor tissue at 12 and 60 hours compared to unmodified bacteria. In both 4T1 and H22 tumor-bearing mouse models, aptamer-conjugated attenuated Salmonella show enhanced antitumor efficacy, along with highly activated immune responses inside the tumor. This work demonstrates how bacterial behaviors can be tuned by surface conjugation and supports the potential of aptamer-conjugated bacteria for both targeted intratumoral localization and enhanced tumor biotherapy. Bacteria-based therapy has shown promise for cancer treatment. To enhance tumor accumulation, here the authors describe the design of tumor specific aptamer-conjugated bacteria, to improve intratumor localization and enhance therapeutic efficacy.

Antibody–drug conjugates have shown considerable promise for treating disease. However, in order to deliver their full potential, sophisticated site-specific conjugation technologies are needed. This Perspective provides an overview of the different methods used for the site-specific attachment of cytotoxic agents to antibodies. Antibody–drug conjugates (ADCs) comprise antibodies covalently attached to highly potent drugs using a variety of conjugation technologies. As therapeutics, they combine the exquisite specificity of antibodies, enabling discrimination between healthy and diseased tissue, with the cell-killing ability of cytotoxic drugs. This powerful and exciting class of targeted therapy has shown considerable promise in the treatment of various cancers with two US Food and Drug Administration approved ADCs currently on the market (Adcetris and Kadcyla) and approximately 40 currently undergoing clinical evaluation. However, most of these ADCs exist as heterogeneous mixtures, which can result in a narrow therapeutic window and have major pharmacokinetic implications. In order for ADCs to deliver their full potential, sophisticated site-specific conjugation technologies to connect the drug to the antibody are vital. This Perspective discusses the strategies currently used for the site-specific construction of ADCs and appraises their merits and disadvantages.

To date, numerous inorganic nanocarriers have been explored for drug delivery systems (DDSs). However, the clinical application of inorganic formulations has often been hindered by their toxicity and failure to biodegrade. We describe here a transformable liquid-metal nanomedicine, based on a core–shell nanosphere composed of a liquid-phase eutectic gallium-indium core and a thiolated polymeric shell. This formulation can be simply produced through a sonication-mediated method with bioconjugation flexibility. The resulting nanoparticles loaded with doxorubicin (Dox) have an average diameter of 107 nm and demonstrate the capability to fuse and subsequently degrade under a mildly acidic condition, which facilitates release of Dox in acidic endosomes after cellular internalization. Equipped with hyaluronic acid, a tumour-targeting ligand, this formulation displays enhanced chemotherapeutic inhibition towards the xenograft tumour-bearing mice. This liquid metal-based DDS with fusible and degradable behaviour under physiological conditions provides a new strategy for engineering theranostic agents with low toxicity. The use of inorganic carriers for drug delivery is often limited by toxicity and persistence of inorganic species in the body. Here, the authors report the use of nanocarriers with a liquid-phase eutectic gallium-indium core capable of delivering doxorubicin and subsequently fusing and degrading under mildly acidic conditions.

Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates the activation of a cancer prodrug, thereby enabling simultaneous chemo-radiotherapy with radiotherapy locally activating a prodrug. In an initial demonstration, we show the activation of a fluorescent probe using this approach. Expanding on this, we show how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib and doxorubicin can be liberated using clinically relevant doses of ionizing radiation. This strategy is different to conventional chemo-radiotherapy radiation, where chemo-sensitization of the cancer takes place so that subsequent radiotherapy is more effective. This approach could enable site-directed chemotherapy, rather than systemic chemotherapy, with ‘real time’ drug decaging at the tumour site. As such, it opens up a new era in targeted and directed chemotherapy.Prodrugs offer one route to treat cancer, but they require activation once they have been delivered to the tumour. Now, a simultaneous chemo-radiotherapy strategy has been demonstrated in mice that uses gamma or X-ray irradiation to locally activate an anticancer prodrug.

Many systemic cancer chemotherapies comprise a combination of drugs, yet all clinically used antibody–drug conjugates (ADCs) contain a single-drug payload. These combination regimens improve treatment outcomes by producing synergistic anticancer effects and slowing the development of drug-resistant cell populations. In an attempt to replicate these regimens and improve the efficacy of targeted therapy, the field of ADCs has moved towards developing techniques that allow for multiple unique payloads to be attached to a single antibody molecule with high homogeneity. However, the methods for generating such constructs—homogeneous multi-payload ADCs—are both numerous and complex owing to the plethora of reactive functional groups that make up the surface of an antibody. Here, by summarizing and comparing the methods of both single- and multi-payload ADC generation and their key preclinical and clinical results, we provide a timely overview of this relatively new area of research. The methods discussed range from branched linker installation to the incorporation of unnatural amino acids, with a generalized comparison tool of the most promising modification strategies also provided. Finally, the successes and challenges of this rapidly growing field are critically evaluated, and from this, future areas of research and development are proposed. Multi-payload antibody–drug conjugates (ADCs) are an emerging class of targeted therapeutics. Comprising a monoclonal antibody with multiple unique payloads attached, these constructs have the potential to produce synergistic anticancer effects with reduced therapeutic resistance. In this Review, methods for generating multi-payload ADCs are discussed, highlighting some key preclinical results.

Nanobodies (Nbs), the smallest antigen-binding fragments with high stability and affinity derived from the variable domain of naturally occurring heavy-chain-only antibodies in camelids, have been shown as an efficient way to improve the specificity to tumors for photodynamic therapy (PDT). Nonetheless, the rapid clearance of Nbs in vivo restricts the accumulation and retention of the photosensitizer at the tumor site causing insufficient therapeutic outcome, especially in large-volume tumors. Herein, we develop photodynamic conjugates, MNB-Pyra Nbs, through site-specific conjugation between 7D12 Nbs and type I photosensitizer MNB-Pyra (morpholine-modified nile blue structure connected to pyrazolinone) in a 1:2 ratio. The photosensitizers with long-term retention can be released at the tumor site by reactive oxygen species cleavage after illumination, accompanied with fluorescence recovery for self-reporting the occurrence of PDT. Ultimately, a single dose of MNB-Pyra Nbs demonstrate highly effective tumor suppression with high biosafety in the large-volume tumor models after three rounds of PDT. This nanobody conjugate provides a paradigm for the design of precise long-time retention photosensitizers and is expected to promote the development of PDT. Cancer therapy with nanobodies (Nbs) is limited by its effective accumulation at the tumor sites. Here the authors develop a Nile blue-based photosensitizer conjugating with pyrazolone-derived Nbs thereby achieving effective retention on tumor sites and suppressing tumor progression through photodynamic therapy.

The prodrug design strategy offers a potent solution for improving therapeutic index and expanding drug targets. However, current prodrug activation designs are mainly responsive to endogenous stimuli, resulting in unintended drug release and systemic toxicity. In this study, we introduce 3-vinyl-6-oxymethyl-tetrazine (voTz) as an all-in-one reagent for modular preparation of tetrazine-caged prodrugs and chemoselective labeling peptides to produce bioorthogonal activable peptide-prodrug conjugates. These stable prodrugs can selectively bind to target cells, facilitating cellular uptake. Subsequent bioorthogonal cleavage reactions trigger prodrug activation, significantly boosting potency against tumor cells while maintaining exceptional off-target safety for normal cells. In vivo studies demonstrate the therapeutic efficacy and safety of this prodrug design approach. Given the broad applicability of functional groups and labeling versatility with voTz, we foresee that this strategy will offer a versatile solution to enhance the therapeutic range of cytotoxic agents and facilitate the development of bioorthogonal activatable biopharmaceuticals and biomaterials. 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.