ABSTRACT Supramolecular chemistry provides an efficient and transformative strategy for the modular integration of diverse active pharmaceutical ingredients (APIs) into nanoassemblies through weak, reversible noncovalent interactions, combining the native features of the original molecules with additional functionalities derived from supramolecular structures. Thanks to ultra‐high photosensitizer or API loading, on‐demand delivery, facile multifunction integration, scalability, and potentially simplified regulatory pathways, supramolecular nanoassemblies markedly enhance the clinical translatability of nanomedicine. In particular, rational design of these systems can overcome hypoxia barriers, revitalizing photodynamic therapy (PDT) against tumors. Despite clinical approval of PDT for cancer therapy over four decades ago, it has yet to achieve widespread adoption as a first‐line modality, largely due to the technological bottleneck of tumor hypoxia. In this review, we systematically summarize recent advances in supramolecular nanoassemblies for hypoxic tumor PDT, categorizing them into four key design principles: enriching intratumoral oxygen levels, minimizing oxygen dependence, leveraging tumor hypoxia, and enabling PDT‐involved synergistic therapies. We also discuss the intrinsic properties, advantages, and building motifs of supramolecular nanoassemblies. Finally, we highlight current challenges and future perspectives, aiming to broaden the research landscape and accelerate clinical and commercial translation.

Tumor response according to the Response Evaluation Criteria in Solid Tumors

The traditional labeling method for targeted NIR fluorescence probes requires directly covalent-bonded conjugation of targeting domains and fluorophores in vitro. Although this strategy works well, it is not sufficient for detecting or treating cancers in vivo, due to steric hindrance effects that relatively large fluorophore molecules exert on the configurations and physiological functions of specific targeting domains. The copper-free, "click-chemistry"-assisted assembly of small molecules in living systems may enhance tumor accumulation of fluorescence probes by improving the binding affinities of the targeting factors. Here, we employed a vascular homing peptide, GEBP11, as a targeting factor for gastric tumors, and we demonstrate its effectiveness for in vivo imaging via click-chemistry-mediated conjugation with fluorescence molecules in tumor xenograft mouse models. This strategy showed higher binding affinities than those of the traditional conjugation method, and our results showed that the tumor accumulation of click-chemistry-mediated probes are 11-fold higher than that of directly labeled probes. The tracking life was prolonged by 12-fold, and uptake of the probes into the kidney was reduced by 6.5-fold. For lesion tumors of different sizes, click-chemistry-mediated probes can achieve sufficient signal-to-background ratios (3.5-5) for in vivo detection, and with diagnostic sensitivity approximately 3.5 times that of traditional labeling probes. The click-chemistry-assisted detection strategy utilizes the advantages of "small molecule" probes while not perturbing their physiological functions; this enables tumor detection with high sensitivity and specific selectivity.

The clinical success of chimeric antigen receptor (CAR) T cell therapy requires scalable, non-invasive strategies for in vivo T cell engineering. Although mRNA delivery offers a promising alternative, lipid-nanoparticle-based carriers show limited efficiency for in vivo T cell transfection and typically require antibody conjugation. Here we report an inherent T cell-activating polymer-lipid nanoparticle that enables ligand-free, efficient mRNA transfection and activation of T cells in vivo. This mRNA delivery vehicle, composed of p-toluenesulfonyl arginine (RT)-modified oligoethylenimine-based lipid nanoparticles (ERTLNPs), preferentially mediated mRNA transfection in the spleen following systemic administration. Without exogenous stimulation, ERTLNPs intrinsically activated T cells, triggering robust mRNA expression and proliferation. Mechanistically, ERTLNPs engaged the PI3K/AKT/mTOR signalling axis to reprogram T cell metabolism, promoting expansion and restraining exhaustion. The systemic delivery of mRNA encoding fibroblast activation protein CAR via ERTLNPs contributed to the in situ generation of functional CAR T cells, which efficiently eliminated pathological fibroblasts in models of cancer and fibrosis, with minimal off-target effects. This ligand-free, metabolically reprogramming mRNA delivery system provides a clinically translatable approach for in vivo CAR T cell generation.

Nanomedicine has revolutionized the landscape of cancer theranostics. However, developing nanodrugs with effective penetration and prolonged retention remains challenging. Here, we report a stimuli-independent transformable nanophotosensitizer (SITNPS), which can transform from thermodynamically metastable nanospheres to stable nanorods, improving tumor penetration and retention. The unique sterically undemanding donor-π-acceptor molecule displays enhanced non-covalent coupling, facilitating SITNPS formation. With robust two-photon-excited characteristics and excellent singlet oxygen generation, SITNPS induces redox homeostasis imbalance, mitochondrial dysfunction, and DNA damage. SITNPS effectively inhibits tumor growth by triggering two-photon or smartphone-torch-activated photodynamic therapy (PDT), overcoming limitations of inadequate light penetration and dependence on specialized equipment. Due to prolonged retention, portable light could be given three times with a single administration, enhancing tumor inhibition compared to clinical photosensitizers. This work presents a promising paradigm of stimuli-independent self-transforming nanophotosensitizers to facilitate practical translation of long-term tumor-retaining nanomedicines and broadens PDT applications in deep-seated tumors with penetrable and portable light sources.

The advancement of precision medicine depends critically on well-defined molecular targets. Pathologically activated fibroblasts drive disease progression in cancer, fibrosis and chronic inflammation through sustained inflammation, extracellular matrix remodeling and pathological microenvironment formation. Among available markers, fibroblast activation protein (FAP) stands out due to its selective overexpression in diseased tissues versus minimal expression in healthy organs. This unique profile makes FAP a promising target for molecular imaging and targeted therapy, enabling precision theranostics across both oncological and nononcological diseases. FAP-targeted theranostics originated from the lead compound PT-100, which established the core pharmacophore. Subsequent key advance was the replacement of the boronic acid warhead with a cyano group, along with the introduction of fluorine and quinoline moieties, yielding the UAMC-1110 scaffold. This scaffold exhibits improved bioactivity and favorable pharmacokinetics. Systematic modification of the quinoline side chain and conjugation with chelators have allowed efficient radiolabeling, positioning radiolabeled FAP inhibitors as promising tools for precision theranostics. However, continued optimization of UAMC-1110-derived probes to enhance their stability, affinity, tumor retention, and cellular uptake, together with integration into advanced strategies such as nanomedicine, remains essential not only for refining FAP-targeted precision medicine but also for expanding its applications beyond oncology to nononcological diseases. Unlike previous reviews, this Account organizes the field around a unified chemical design language, following a "rational design-pharmacokinetics-translational validation" paradigm. After delineating the core biological functions of FAP-expressing fibroblasts in disease pathogenesis, we systematically examine the rapid advancement of radionuclide-labeled FAPIs, including optimization of linkers, chelators, and albumin-binding moieties, along with multimerization strategies, which significantly enhanced the pharmacokinetic profiles. Key innovations in the field include three strategic approaches. First, the albumin-binding therapeutic agent [177Lu]Lu-EB-FAPI achieves prolonged tumor retention and promising efficacy. Second, multimerization strategies have yielded bivalent and tetrameric FAPI constructs, which exhibit superior tumor accumulation. Third, heterodimeric probes such as [68Ga]Ga-FAPI-RGD and [68Ga]Ga-FAPI-LM3 enable dual targeting of FAP along with integrin αvβ3 or somatostatin receptor SSTR2, thereby addressing tumor heterogeneity and enhancing lesion detectability. Subsequently, the application scope of FAPI-based imaging has been expanded from oncology to nononcological diseases. The value of this technique in visualizing dynamic remodeling processes across key pathologic conditions has been established, offering quantitative assessment beyond the reach of standard modalities. Furthermore, we review recent advances in diverse FAP-targeted therapeutic strategies, including nanomaterials, CAR-T cells, and vaccines, and offer a forward-looking perspective on both the potential and the ongoing challenges of FAP as a cross-disease precision theranostic platform.

Uncontrollable traumatic bleeding is the leading cause of trauma-related mortality, and hemostatic materials play a vital role in saving lives. However, it remains challenging to develop multifunctional hemostatic materials integrating ultra-rapid hemostasis, strong tissue adhesion, and wound healing promotion. Inspired by natural superabsorbent biological systems, we engineered a superporous chitosan sponge (M-SCS) via programmed freeze-drying. The sponge features a hierarchical capillary network for instantaneous liquid uptake, while within the confined stable chitosan 3D framework, hydrophilic quaternized chitosan phenylboronic acid (MBACS) chains undergo confined gelation, rapidly transforming the absorbed blood into a robust hydrospongel. Specifically, M-SCS30 swells 3.2 ± 0.2-fold immediately upon water uptake, with an absorption rate of 26.7 ± 1.4 g/(g·s) and a maximum water capacity of 114.3 g/g, outperforming current analogous studies. The synergistic effect of superabsorbency and MBACS endows M-SCS30 with rapid coagulation (within 10 s) and strong tissue adhesion. In a non-compressive liver injury model, the dressing achieves hemostasis within 20 s, reducing blood loss from 301 ± 6.0 mg (commercial CELOX-E group) to 25 ± 3.0 mg. In infected wounds, it inhibits infection and accelerates healing. Overall, this study offers key insights for advancing the development of superabsorbent materials and multifunctional high-performance hemostatic materials.

The success of mRNA vaccines has motivated the development of mRNA therapeutics to treat a wide range of diseases, as well as applications in regenerative medicine. However, the inherent instability of mRNA under conditions of oxidative stress renders these applications challenging. Here we report a general approach to shield mRNA from oxidative degradation by incorporating antioxidant lipid within lipid nanoparticles (LNPs). Specifically, we design a library of antioxidant ionizable lipids and identify a lead LNP formulation containing a 4-hydroxyphenyl-modified antioxidant lipid. Mechanistically, we show that antioxidant LNPs directly scavenge reactive species and preserve mRNA integrity under extracellular and intracellular oxidative stress. Across multiple organ and tissue injury models, we demonstrate that AO12LNPs sustain high-level and durable protein expression and restore higher transcript integrity than conventional clinically used LNPs, leading to improved regenerative outcomes and more efficient genome editing. Our findings highlight the potential of AOLNPs as a next-generation mRNA delivery platform, capable of overcoming challenging oxidative conditions in regenerative medicine.

Pancreatic adenocarcinoma is a highly aggressive malignancy with a poor prognosis, largely due to its dense and immunosuppressive tumor microenvironment (TME) and resistance to conventional therapies. Although targeted radionuclide therapy (TRT) and immune checkpoint blockade (ICB) have demonstrated clinical success in other malignancies, their efficacy in pancreatic adenocarcinoma remains limited. This study evaluated a combination strategy integrating fibroblast activation protein (FAP)–targeted TRT—using either ¹⁷⁷Lu-LNC1004 or ²²⁵Ac-LNC1004—with anti-PD-L1 ICB to overcome stromal barriers and enhance antitumor immunity. The FAP-targeted ligand LNC1004 was radiolabeled with ¹⁷⁷Lu (β-emitter) or ²²⁵Ac (α-emitter). Biodistribution and tumor uptake were assessed in Panc02 tumor–bearing mice using SPECT/CT imaging (n = 3) and ex vivo analysis (n = 4). Therapeutic efficacy was evaluated in tumor-bearing mice treated with ¹⁷⁷Lu-LNC1004, ²²⁵Ac-LNC1004, anti-PD-L1 monoclonal antibody, or combination regimens (n = 8 per group). Immune profiling of tumor tissue and peripheral blood was performed by flow cytometry to assess PD-L1 expression, T-cell subsets, and interferon-γ (IFNγ) levels. ¹⁷⁷Lu-LNC1004 demonstrated prolonged tumor retention and high tumor-to-background ratios in Panc02 xenografts. Combination therapy with ¹⁷⁷Lu-LNC1004 (30 MBq) and anti-PD-L1 resulted in complete tumor regression throughout a 40-day observation period, outperforming all monotherapy groups. Sequential therapy with ²²⁵Ac-LNC1004 (37 kBq) and anti-PD-L1 achieved durable responses, with complete tumor eradication observed in 6 of 9 mice over more than 90 days of follow-up. All treatment regimens were well tolerated, with only transient and reversible body-weight loss.

Fibroblast activation protein (FAP)-targeted radiotheranostics show strong promise for cancer imaging and therapy, yet their clinical translation is limited by the trade-off between rapid tumor targeting and insufficient systemic residence time. To address this challenge, we report the design and evaluation of 177Lu-Albb-2FAPI, a long-acting dimeric FAPI derivative that integrates FAPI-02 dimerization with an Evans Blue-based reversible albumin-binding motif to achieve improved tumor targeting while preserving a favorable pharmacokinetic profile. Molecular docking revealed enhanced FAP binding via avidity-driven stabilization without compromising albumin interaction. In vitro studies confirmed rapid, FAP-specific cellular uptake, while in vivo SPECT/CT imaging and biodistribution analyses demonstrated higher and more sustained tumor accumulation, together with improved early tumor-to-background contrast, compared with the monomeric analogue Albb-1FAPI. In the Panc02 tumor model, characterized by moderate FAP expression, 177Lu-Albb-2FAPI exhibited durable tumor retention and induced rapid tumor regression while preserving hematological safety. By coupling dimerization-enhanced target engagement with controlled albumin binding, 177Lu-Albb-2FAPI overcomes key diagnostic and therapeutic limitations of existing long-acting FAP radioligands, establishing a refined molecular design strategy for next-generation FAP-targeted radiotheranostics with strong translational potential.

In situ therapeutic agent production strategy is promising to overcome the drawbacks of direct drug delivery. Hypoxia provides a great target for precise treatment of tumor. Here we report a copper ion competition-based nanoparticle (NP) for hypoxia-activated formation of diethyldithiocarbamate (DTC)-copper complex, an immunogenic cell death (ICD) inducer. The NP is composed of an amphiphilic hypoxia-responsive DTC precursor and a fluorescence quenched copper ion-chelated squaric acid. In hypoxic tumor cells, the azobenzene linker in DTC precursor can be cleaved through bioreduction, leading to DTC release and subsequent copper ion exchange between DTC and squaric acid. Simultaneous formation of toxic DTC-copper complexes and fluorescence recovery will allow for visualization of in situ therapeutic agents production. Furthermore, the DTC-copper complexes can induce ICD and promote cytotoxic T lymphocyte infiltration for cancer immunotherapy. This study not only provides a promising hypoxia-activated nanomedicine for precision cancer therapy, but also a visualization strategy for evaluating the treatment process.

[This corrects the article DOI: 10.7150/thno.92991.].

INTRODUCTION:The post-infarction microenvironment, dominated by oxidative stress, hypoxia, and dysregulated inflammation, severely limits cardiac regeneration. Existing injectable hydrogels for myocardial infarction (MI) rarely address these factors simultaneously, and excessive reactive oxygen species (ROS) scavenging may paradoxically cause oxidative damage. OBJECTIVES:To develop an injectable hydrogel capable of concurrently scavenging ROS, sustaining oxygen release, and modulating immune responses without inducing oxidative damage. METHODS:A chitosan oligosaccharide-hyaluronic acid hydrogel (C-COS-OHA) was synthesized, incorporating a mild Fe3+/adenosine monophosphate (AMP) nano-enzyme for oxygen generation and redox stability. Carboxyl-modified chitosan oligosaccharide (C-COS) was designed to promote M2 macrophage polarization. The hydrogel was evaluated in vitro for oxidative stress protection and hypoxia tolerance, and in MI mouse models for oxygen retention, inflammation modulation, and cardiac repair. RESULTS:Compared with catalase (CAT)-loaded hydrogels, C-COS-OHA-Fe3+/AMP enhanced HUVEC survival by 28.9% under oxidative stress and accelerated scratch closure by 26.9% under hypoxia. In vivo, photoacoustic imaging confirmed prolonged oxygen retention; qRT-PCR revealed a 4.1-fold increase in TGF-β expression. After 28  days, MI mice showed 49% reduced fibrosis, 37% thicker ventricular walls, and improved left ventricular ejection fraction (58.3 ± 3.1%), all exceeding C-COS-OHA-CAT performance. CONCLUSION:The C-COS-OHA-Fe3++/AMP hydrogel integrates ROS scavenging, oxygen modulation, and immunoregulation into a single injectable platform, representing a shift from single-mechanism MI hydrogels to comprehensive microenvironmental regulation for enhanced cardiac regeneration.

The application of messenger RNA (mRNA) beyond infectious diseases is challenged by inefficient protein production. Whereas the engineering of secondary mRNA structures has been shown to increase mRNA half-life, it remains unclear whether tertiary mRNA structures influence therapeutic efficacy. Here we develop a metal-ion-assisted RNA folding (MARF) strategy and show that, when delivered with lipid nanoparticles (LNPs), specific metals promote mRNA folding architectures that result in the amplification of protein expression by up to 7.3-fold compared with control mRNA. This effect is due to altered mechanical interactions between the mRNA LNPs and the surrounding biosystem, resulting in enhanced intracellular processing and prolonged retention of delivered mRNA in targeted cells. Administered intravenously, MARF LNPs achieved effective and durable genome editing of the clinically relevant Pcsk9 gene through treatment with a single dose. Overall, this work provides a new MARF technology for more effective mRNA therapy and highlights the potential of mechanical cues in designing nanoparticles for improved mRNA delivery.