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Antibody-drug conjugates (ADCs) represent a major advance in precision cancer therapy by combining the high target specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule payloads through chemical linkers. Among the payload classes topoisomerase I (Topo I) inhibitors, camptothecin and its derivatives have emerged as highly promising warheads owing to their distinct mechanism of action and strong antitumor activity. The clinical success of Enhertu and Trodelvy, which employ the camptothecin-derived payloads DXd and SN-38, respectively, has validated the therapeutic potential of camptothecin-based ADCs and accelerated the development of next-generation candidates. This review summarizes recent progress in camptothecin-based ADCs since 2021, with a focus on strategies for payload modification of camptothecin derivatives, and linker optimization. In addition, current limitations of camptothecin-based ADCs, including resistance and insufficient efficacy, are discussed together with emerging solutions such as combination strategies and dual-payload ADCs. This review is expected to provide a useful framework for the rational design and further development of camptothecin-based ADCs.

Antibody-drug conjugates (ADCs) are rapidly evolving from conventional cytotoxic delivery systems into multifunctional, immune-integrated therapeutic platforms. Highlights from the 2026 American Association for Cancer Research (AACR) Annual Meeting demonstrate significant advances in ADC design, including dual- and multi-payload constructs, multispecific targeting strategies, and immunostimulatory payloads. These innovations aim to overcome key limitations such as tumor heterogeneity, resistance, and systemic toxicity. Novel approaches targeting the tumor microenvironment, including depletion of regulatory T cells and tumor-associated macrophages, further expand the therapeutic scope of ADCs beyond direct tumor cell killing. In parallel, integration with emerging modalities such as engineered CD16-enhanced natural killer T (NKT) cells underscores the potential for synergy between ADCs and cellular immunotherapies. Advances in AI-guided target discovery and antibody engineering are also enhancing tumor selectivity and internalization. Collectively, these developments highlight a paradigm shift toward precision, multi-mechanistic ADCs with the potential to improve clinical outcomes across diverse cancer types.

Antibody-drug conjugate (ADC) payload discovery remains constrained by reliance on traditional molecular descriptors that inadequately capture three-dimensional geometric features governing target recognition and mechanism of action. Topological data analysis (TDA) offers a mathematical framework for characterizing molecular shape through persistent homology, potentially revealing mechanistic relationships invisible to conventional approaches. We developed a comprehensive TDA framework analyzing 22 FDA-approved ADC payloads across 1,471 clinical trial records, computing 31 topological descriptors encompassing Betti numbers, persistence statistics, and complexity metrics. Hierarchical clustering, principal component analysis, and correlation network analysis were employed for dimensionality reduction and cluster validation, with molecular docking studies validating TDA-derived classifications. TDA-based clustering identified eight distinct payload classes with excellent separation. Principal components captured 79.8% of topological variance, with Betti numbers and persistence lifetime as dominant features. Three major mechanistic clusters emerged: vinca alkaloids (tubulin inhibitors), camptothecins (topoisomerase I poisons), and DNA alkylators. Molecular docking demonstrated high performance within-cluster binding consistency and significant cross-cluster discrimination. We establish the first validated TDA framework for ADC payload discovery, demonstrating that persistent homology captures biologically meaningful mechanistic classifications suitable for rational payload design and mechanism-of-action prediction in precision oncology.

Antibody-drug conjugates (ADCs) represent a rapidly evolving therapeutic modality, combining the selective targeting of monoclonal antibodies with highly potent small molecule payloads. Their inherent structural complexity demands a sophisticated and multi-faceted bioanalytical approach spanning preclinical discovery through late-stage clinical development. This white paper, developed by the ADC Working Group of the AAPS bioanalytical community, comprising over 100 members from industry, contract research organizations (CROs), and regulatory agencies, provides updated recommendations for ADC bioanalysis. Building upon the foundational 2013 AAPS position paper and recent publications governing regulatory frameworks on PK considerations, this work addresses advances in bioanalytical quantitation strategies for total antibody (tAb), conjugated ADC, free (unconjugated) payload, and drug-to antibody ratio (DAR); novel immunogenicity assessment considerations; soluble target interference; critical reagent lifecycle management; payload-specific stability requirements; cross-validation strategies; and regulatory considerations. The recommendations presented herein reflect over a decade of scientific progress and are designed to serve as a comprehensive, empirically validated, and industry aligned bioanalytical framework for contemporary ADC drug development.

Advanced colorectal cancer (CRC) has limited therapeutic options. Antibody-drug conjugates (ADCs) deliver cytotoxic agents selectively, minimizing systemic toxicity. This study outlines the current clinical trial landscape of ADCs in CRC to identify research gaps and future directions. We queried the Trialtrove database (up to August 2025) for non-observational trials of ADCs in CRC. Analytical indicators included temporal trends, geographic distribution, sponsor type, target antigens, and payloads. Overall, 194 eligible trials were identified. Trial numbers have steadily increased since 2020, peaking in 2024. Most are open trials, predominantly conducted in China and the United States, and heavily industry-sponsored. HER2, Trop-2, and c-Met are the most frequently studied targets. Topoisomerase I inhibitors are the most common payloads, frequently paired with cleavable linkers. Crucially, the vast majority of these trials remain in early phases (Phase I/II), with Safety and tolerability remaining the primary endpoints. ADCs show preliminary therapeutic potential in CRC; however, assertions regarding broad efficacy must remain highly cautious given the early-stage, safety-oriented nature of the current pipeline. Furthermore, the current landscape faces challenges such as publication bias and industry dominance, which prioritize commercially viable hotspots over niche targets. Future progress relies on discovering novel targets, optimizing linker-payload designs, and exploring rational combination therapies.

Treating bone defects becomes particularly challenging when drug-resistant bacteria take hold. Standard antibiotics often fail to clear these infections completely, and the resulting inflammatory environment actively blocks new bone formation. To tackle this problem, we developed a sulfonated-PEEK scaffold called SPMiL that carries two distinct payloads: the human derived antimicrobial peptide LL37 and mitochondria-rich vesicles (EV-Mito). We generated these vesicles from ectomesenchymal stem cells (EMSCs) lacking Opa1, a key regulator of mitochondrial dynamics. Knocking out this gene substantially boosts vesicle production, solving the supply limitations that have hampered previous attempts to use EV-Mito therapeutically. In tests using MRSA-infected rat calvarial defects, SPMiL released LL37 continuously to eliminate the resistant bacteria while simultaneously transferring functional mitochondria into recipient cells. These transplanted organelles promoted osteogenic differentiation and suppressed osteoclast activity through metabolic reprogramming, antioxidant effects, and restoration of mitochondrial membrane potential. This work demonstrates that combining antibacterial defense with mitochondrial transfer offers a viable approach for treating infected bone defects that resist conventional treatment.

The programmed death-1 (PD-1) immune checkpoint is a core regulator of T-cell exhaustion and immune evasion in cancer. While PD-1/PD-L1 monoclonal antibodies have changed the landscape of cancer immunotherapy, there are barriers to broader application due to their large size, potential for systemic toxicities, and high production costs. In this review article, we will focus on therapeutic development, functional applications, and translational advances of anti-PD-1 single-chain variable fragments (scFvs). Advances in phage-display libraries, immunization methods, and antibody engineering have helped develop high-affinity scFvs with novel structural and mechanistic properties. Direct functional applications incorporating anti-PD-1 scFvs are bispecific and trispecific constructs, antibody-drug conjugates (ADCs), immunotoxins, nanoparticles, and biological vector carriers that incorporate checkpoint blockade with targeted cytotoxicity or immunostimulation. Engineered immune cells, such as armored CAR-Ts, NK cells, and MSCs, can secrete or display anti-PD-1 scFvs within the tumor to provide localized checkpoint inhibition, enhance effector-cell persistence, and remodel the tumor microenvironment. Oncolytic and non-replicating viral vectors can further confine scFv activity to tumors, coupling checkpoint blockade with oncolysis, cytokine expression, or bispecific T-cell engagers. Early-phase clinical trials are currently studying TILs and CAR-TILs engineered to secrete scFvs and oncolytic HSV-1 encoding multifunctional checkpoint payloads across a variety of solid tumors. Taken together, anti-PD-1 scFvs represent a modular platform for localized checkpoint inhibition and potentially improved cost-effectiveness compared with systemic antibodies. Future work should prioritize rational combination strategies and well-designed clinical trials that integrate anti-PD-1 scFv platforms with other immunotherapies and standard treatments to maximize clinical benefit.

Stimuli-responsive micro/nanocontainers play a vital role in targeted delivery for protective coatings. Achieving precise functions necessitates a new generation of materials capable of stepwise-controlled release of multiple payloads. However, co-encapsulating diverse active agents poses challenges, particularly in achieving sequential release, critical for advancing complex protective strategies. Herein, hierarchical MOF-on-MOF core-shell containers were constructed by mild epitaxial growth to spatially accommodate corrosion inhibitors and warning agents. The ZIF-67@ZIF-8 system showed a two-stage release profile, with preferential MBT release from the less stable ZIF-67 core followed by delayed BTA release from the ZIF-8 shell. Comparatively, the parallel ZIF-8@ZIF-8 architecture exhibited largely overlapped release profiles. This observation suggests that core-shell construction alone does not guarantee staged release and that framework stability contrast is an important factor in regulating temporal delivery. When incorporated into epoxy coatings, the inhibitor-loaded containers enhanced defect-site corrosion protection on Cu and Al substrates, while Phen-containing containers enabled colorimetric warning on Fe-based substrates. This work demonstrates a stability-gradient strategy for temporally programmed delivery in multifunctional corrosion-protective coatings.

Oral squamous cell carcinoma (OSCC) is a serious malignancy characterised by poor outcomes, late identification, therapeutic resistance, and the adverse effects associated with radiation therapy, surgery, and chemotherapy. Nanotechnology-based drug delivery provides modular approaches that improve intratumoral accumulation, safeguard payloads, and facilitate controlled release, all while reducing off-target damage. This review compiles the latest findings in the field of oral cancer targeting magnetic nanomaterials, cyclodextrins, quantum dots, dendrimers, and metallic/inorganic platforms (metal-organic frameworks). Mechanistic innovations encompass both passive and active targeting strategies (e.g., EGFR, folate, CD44), stimuliresponsive mechanisms (pH, enzyme), and precision systems guided by salivary biomarkers (e.g., IL-8, CYFRA 21-1), ultimately leading to enhanced therapeutic indices and real-time theranostic monitoring. Innovative approaches use AI-driven design, biosensor-facilitated early detection, and Nanovaccine/immunenanomedicine techniques to personalise treatment in the multifaceted oral tumour microenvironment. Translational challenges remain, including heterogeneous EPR effects, nanotoxicology (encompassing autophagy and ROS pathways), manufacturing scale-up, and regulatory standardisation. These issues require the development of robust pharmacology-toxicity frameworks and biomarker-driven clinical trials. Nanocarriers of the future may revolutionise OSCC treatment by bringing together materials science, tumour biology, and genetic and salivary signals that are unique to each patient. This will allow for safer, more effective, and quantifiable precision therapies.

Personalized oncology is hindered by limited tumor selectivity and intracellular delivery of cytotoxics. A receptor-targeted strategy addresses this by conjugating anticancer drugs to peptide ligands that bind selectively to receptors enriched on malignant cells. Sortilin (SORT1; neurotensin receptor-3) is a scavenger receptor overexpressed across multiple aggressive cancers and correlates with tumor grade, making it a clinically attractive entry point for targeted delivery. A peptide conjugation platform using a proprietary SORT1-binding sequence (TH19P01) enabled the creation of peptide-drug conjugates (PDCs) with Docetaxel, Doxorubicin, and Camptothecin, facilitating a vectorization approach to enhance tumor selectivity and drug delivery efficay. In vitro, these PDCs accumulated intracellularly in a SORT1-dependent manner, overcame chemoresistance linked to P‑glycoprotein efflux and to vasculogenic mimicry, selectively targeted cancer stem cells, and enhanced immune cell infiltration. In vivo, they showed improved tolerability and stronger inhibition of tumor xenografts versus unconjugated drugs. These preclinical data underpin a phase‑1 trial of Sudocetaxel Zendusortide (TH1902), which has achieved clinically meaningful, durable disease stabilization. Collectively, the work positions SORT1 as a functional hub in tumor aggressiveness and resistance, and establishes SORT1‑directed PDCs as a new precision oncology class. The platform is scalable across payloads, tumor types, and combination regimens, offering a unified approach to simultaneously tackle drug resistance, cancer stem cell persistence, tumor vascular mimicry, and immune evasion.

Chimeric antigen receptor (CAR) T-cell therapy has transformed hematological cancer care, yet variability in efficacy, durability, and safety cannot be explained solely by antigen selection or patient factors. We propose that manufacturing platforms are active biological determinants of outcome. Viral vectors, used in all licensed products, provide stable genomic integration and durable expression but are limited by cost, cargo capacity, and centralized production. Nonviral strategies, including transposons, CRISPR knock-ins, and messenger RNA delivery, enable faster, less-expensive manufacturing with larger payloads, while introducing distinct safety and persistence profiles. This review presents a three-layer mechanistic framework that reframes manufacturing as biology: integration biology determines genomic risk and transgene stability; clonal fitness shapes persistence, dominance, and exhaustion; and epigenomic imprinting, influenced by gene transfer method, cytokines, and culture stress, preconfigures functional trajectories. Clinical observations link platform choice to immune recovery, where prolonged B-cell aplasia and delayed T-cell reconstitution contribute to infection-related nonrelapse mortality, and hematopoietic reserve at apheresis emerges as a practical predictor. Finally, manufacturing is positioned as the key to democratizing cell therapy. Decentralized, nonviral production aligned with regulatory standards may enable equitable access and transition CAR-T therapy from innovation to sustainable global care.

Soft robotic grippers, with their intrinsic compliance and dexterity, provide safer manipulation of soft and fragile items compared to traditional rigid ones. However, achieving high functional integration within a single soft gripper, particularly for cross-scale, multi-particle, and high-load manipulation, remains a major challenge. Here, a monolithically 3D-printed, rapeseed-flower-inspired self-reconfigurable soft gripper (SRSG) is presented, which can rapidly reconfigure its finger arrangement within ∼130 ms and achieves precise, reversible switching between diagonal and parallel configurations. The SRSG can be readily incorporated with detachable petal modules to alter the grasping workspace. Leveraging these capabilities enables a range of functions: rotating bulbs of varying diameters, picking fruits, grasping cross-scale objects ranging from 0.07 to 270 mm (grasping range ratio of ∼3857 times), lifting payloads up to 5.6 kg (∼106 times its own weight), and adaptively enveloping numerous fine particles, multiple live aquatic organisms, and fragile underwater targets. The fully soft, electronics-free SRSG establishes a self-reconfigurable grasping paradigm for robust operation in unstructured environments, and opens up new directions for soft robotic end-effectors.

Precise control over how and where small-molecule drugs are covalently attached to monoclonal antibodies is increasingly vital for creating consistently efficacious and safe antibody-drug conjugates (ADCs) as powerful targeted therapies. Enzymatic conjugation methods have gained considerable attention for their abilities to efficiently install payloads at defined locations under mild and predictable conditions. This work provides a comprehensive review of current enzymatic technologies for site-specific ADC construction, organized by the biological origin of enzymes. Among various enzyme-based conjugating approaches, a special focus is given to the emerging ADP-ribosyl cyclase-enabled ADC (ARC-ADC) platform. By utilizing genetically fused CD38, a member of the ARC family, together with its dinucleotide-derived inhibitor, site-specific ADCs with defined drug-to-antibody ratios in varied formats could be facilely produced with demonstrated efficacy and specificity in preclinical models of different types of cancer. Unlike most enzymatic methods requiring recognition tags or external catalytic steps, ARC-ADC provides a fully integrated, modular strategy for streamlined ADC discovery and development.

The wide-ranging impact of the human microbiome on health and disease has sparked growing interest in employing bacteria as live therapeutics. Natural properties of bacteria have been enhanced using synthetic biology to treat diverse diseases, from infections to inflammation and cancer. However, a major obstacle in this area is identifying specific bacterial hosts and molecular payloads that are both safe and effective for specific diseases or cancers. In this study, we explored environmental microbial diversity as a promising source of new therapeutic agents that could be engineered for bacterial drug delivery systems. We collected and characterized soil bacteria from 25 urban public parks, then evaluated their secreted metabolites for anti-cancer activity using both monolayer and three-dimensional spheroid models of lung cancer. Metagenomic analysis, toxicity profiling, and co-culture assays revealed that several Bacillus species isolated from Manhattan park soils produced compounds with strong, dose-dependent cytotoxic effects on lung cancer cells. Furthermore, we demonstrated that Bacillus subtilis-a well-characterized, gram-positive model organism-was capable of colonizing lung tumor spheroids, suggesting its potential as a safe and effective chassis for bacterial cancer therapy. Complementing these experiments, we developed a mechanistic ordinary differential equation (ODE) model of the bacteria-spheroid co-culture that is consistent with our bacterial and spheroid growth data. Overall, our findings highlight a discovery platform for the screening of environmental microbes as chassis or payload sources for microbial cancer therapies.

Cadherin-17 (CDH17) is a cell-adhesion molecule physiologically expressed along the intestinal epithelial tight junctions. Aberrant overexpression of CDH17 in gastrointestinal (GI) cancers promotes tumor growth and metastasis and is associated with poor patient prognosis. Due to its restricted expression in normal tissues and strong association with malignancy, CDH17 represents an emerging therapeutic target for GI tract cancers. A high-affinity anti-CDH17 monoclonal antibody (TAVO307) was generated and conjugated with auristatin-derived cytotoxic payloads to obtain CDH17-directed antibody-drug conjugates (ADCs). In parallel, a VHH antibody capable of activating γδ T cell receptors from both Vδ1 and Vδ2 subsets was identified and combined with the anti-CDH17 antibody to generate CDH17-targeted T cell engager (TCE) to recruit γδ T cells, which are abundant in the intestinal mucosa and play a critical role in tumor immunosurveillance. An attenuated interleukin-15 (IL-15) fused with the IL-15 receptor α sushi domain was further incorporated on TCE to enhance γδ T cell expansion and activation. CDH17-based ADCs exhibited potent and selective cytotoxicity in multiple GI cancer cell lines and significant tumor regression in xenograft models. The CDH17 γδ TCE induced tumor antigen-dependent γδ T cell degranulation and redirected both Vδ1 and Vδ2 T cells to effectively kill CDH17-expressing cancer cells. IL-15 fusion further augmented γδ T cell expansion and activation. Both CDH17-targeted ADCs and γδ TCEs demonstrated promising potency and efficacy to control GI cancers. They could offer complementary therapeutic options that could be used in combination therapy.

Antibody-oligonucleotide conjugates (AOCs) have emerged as a promising therapeutic platform that integrates the targeting capability of antibodies with the gene-regulatory potential of oligonucleotide payloads. By enabling cell or tissue selective delivery, AOCs may extend oligonucleotide therapeutics beyond liver predominant distribution and broaden intervention strategies for intracellular targets that have historically been difficult to drug. However, their therapeutic performance is not determined by target binding alone, but also by productive intracellular delivery, including receptor mediated uptake, endosomal trafficking, payload release, and functional access to cytoplasmic or nuclear compartments. In this review, we summarize the key design principles governing AOCs performance, including target biology, antibody formats, oligonucleotide payload classes, chemical modifications, linker design, conjugation strategies, and critical quality attributes. We further discuss the intracellular fate of AOCs and highlight endosomal escape as a major rate limiting step that often constrains biological activity despite efficient cellular uptake. In addition, we review current translational progress, with particular emphasis on neuromuscular disorders, as well as emerging applications in oncology, central nervous system diseases, and other indications. Finally, we outline major challenges and future directions that are likely to shape the next generation of AOCs therapeutics.

Leukaemia, a widespread haematological cancer, possesses particular challenges in theranostics despite the availability of traditional and modern approaches. This article addresses a significant gap in the literature, where a focus on polymeric and hybrid nanoparticles (P&HNP) is lacking in advancing leukaemia therapy, and explores how to overcome limitations of conventional therapeutic approaches. The rationale of this study stems from several considerations, including the fact that while polymeric nanoparticles show promise in leukaemia theranostics, a comprehensive assessment of how biomaterial choices influence therapeutic efficacy remains lacking. This article briefly describes conventional challenges in leukaemia theranostics, followed by the properties of P&HNP that make them potential candidates for leukaemia management. In addition, an understanding of the distinctions between natural (e.g., chitosan) and synthetic polymers (e.g., polyethene glycol), as well as their capacity to integrate targeting ligands, imaging agents, and therapeutic payloads, is essential for the rational design of next-generation treatments. Indeed, hybrid nanosystems that combine polymers with metallic nanoparticles (e.g., Au, Ag, Fe, and Zn) represent an emerging frontier, as noted. Next, the current status and clinical outcomes of P&HNP-based formulations are presented, along with their limitations and solutions to advance them as advanced therapies. Finally, challenges or obstacles that limit the translation perspective of laboratory-designed nanomedicine were addressed. This review identifies promising directions, including innovative nanoparticle designs and combination therapies, that may transform leukaemia treatment paradigms and improve patient survival.

Peptide-drug conjugates (PDC) have recently garnered substantial attention as promising strategies for targeted tumor therapy. However, the clinical efficacy of PDC is limited by poor membrane permeability and inherent lysosomal sequestration. Herein, we report an in-situ cascade assembled peptide-drug conjugate (ISCA-PDC) accomplished by integrating CXCR4-targeting cyclic peptide (Cyclo(DTyr-NMe-DOrn-Arg-2Nal-Gly)), a lysosomal-triggered assembled peptide linker (VEALYL) decorated with pH-sensitive moiety (cis-aconitic anhydride, CAA), and cytotoxic payload (camptothecin, CPT), to improve the tumor membrane permeability and realize lysosomal destabilization, ultimately enhancing the chemotherapy of bladder cancer. In the acidic microenvironment (pH 6.5) of the tumor, ISCA-PDC could first self-assemble into nanoparticles (NPs-PDC) after the hydrolysis of CAA and quickly enter the lysosome via CXCR4-mediated endocytosis to improve tumor membrane permeability. Following transformation into nanofibers (NFs-PDC) within lysosomes (pH 5.0), the permeability of the lysosomes was markedly enhanced, resulting in cathepsin B-induced apoptosis and CPT release. In addition, ISCA-PDC exhibited highly potent antitumor efficacy, which extended the overall survival of tumor recurrence model mice and led to the eradication and regression of T24-luc orthotopic xenograft mice. The concept of in-situ cascade-assembled PDC can be extended by conjugation with other chemotherapeutic agents, suggesting a generalizable strategy for nanotherapeutic enhancement in solid tumors.

Tagraxofusp is a CD123-targeted therapy comprised of a recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin payload. It is the first approved treatment specifically for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). To identify biomarkers of response, bone marrow samples from 12 BPDCN patients who were treated with tagraxofusp in the pivotal phase II trial (NCT02113982) were profiled longitudinally using a gene panel and single-cell RNA sequencing. Residual tumor cells following tagraxofusp expressed lower levels of TXNRD1 that would reduce the efficacy of tagraxofusp. In support of this, enzymatic inhibition of TXNRD1 resulted in higher viability of CAL-1 BPDCN cells following tagraxofusp. Responders had either wild-type or missense TET2 mutations, while transient and non-responders had at least one truncating TET2 mutation. Examples of these mutations within the catalytic domain of TET2 were constructed and transduced into cells. Missense and truncating mutants displayed reduced sensitivities to hypomethylating agents and prolonged S-phase stasis. These results suggest that the levels of TXNRD1 interact with intrinsic TET2 truncating mutations within the bone marrow to modulate patient response to tagraxofusp.