Stimuli-Responsive Zirconium-Based Metal–Organic Frameworks for Targeted Cancer Drug Delivery

Abstract

Metal–organic frameworks (MOFs) have emerged as versatile nanoplatforms for cancer drug delivery owing to their exceptionally high porosity, tunable pore architecture, modular composition, and flexible surface chemistry. In particular, zirconium-based MOFs (Zr-MOFs) have gained considerable attention owing to their good chemical stability, favorable biocompatibility, and ease of functional modification through coordination interactions. These attributes enable precise control over drug loading, surface functionalization, and stimulus-triggered release behavior. Recent advances in stimuli-responsive Zr-MOFs have enabled precise and tumor-selective drug delivery by utilizing intrinsic features of the tumor microenvironment (TME), such as acidic pH, redox gradients, elevated ATP levels, abnormal enzyme activity, and ionic variations, along with externally applied triggers, including light, heat, and ultrasound. This review presents a comprehensive and systematic overview of endogenous, exogenous, and multistimuli-responsive Zr-MOF nanoplatforms for targeted cancer drug delivery. We discuss key Zr-MOF structural families, design strategies for stimulus-responsive behavior, and the underlying structure-stimulus-function relationships that govern therapeutic performance. Representative examples are critically analyzed with respect to drug loading capacity, release mechanisms, targeting strategies, and in vitro and in vivo anticancer efficacy. Additionally, current limitations, including biosafety concerns, degradation behavior, tumor heterogeneity, and barriers to clinical translation, are addressed. Finally, future perspectives are outlined to support the rational development of next-generation Zr-MOF-based nanomedicines with improved precision, controllability, and clinical applicability.

1. Introduction

Cancer continues to be a major global cause of death, and although chemotherapy remains a primary treatment strategy, its clinical effectiveness is frequently limited by issues such as systemic toxicity, suboptimal pharmacokinetics, and poor distribution within tumor tissues. To overcome these limitations, a variety of nanocarrier systems, including liposomes, micelles, dendrimers, mesoporous silica, and metallic nanoparticles, have been extensively investigated. − However, many of these platforms suffer from limited drug-loading capacity, insufficient biodegradability, or long-term toxicity concerns. − In this regard, metal–organic frameworks (MOFs), which are porous crystalline materials constructed from metal nodes and organic linkers, have emerged as promising alternatives for cancer nanomedicine (Figure a-b). Their high surface area, adjustable porosity, structural versatility, and ease of surface modification enable efficient drug encapsulation and controlled release. These attributes enable precise control over drug loading and release and allow MOFs to achieve substantially higher drug-loading capacities than conventional nanocarriers, exemplified by folic acid-modified PCN-777, which exhibited a drug loading of ∼50 wt % with sustained release over 48 h, highlighting the promise of MOFs for long-acting cancer therapeutics.

1.

(a) Schematic illustration of the MOF construction from metal nodes and organic ligands. Created with BioRender.com. (b) Year-wise publication trends of MOFs in cancer drug delivery, Zr-MOFs in drug delivery, and Zr-MOFs in cancer drug delivery. A broken y-axis is applied to improve visualization of lower publication counts. Data were retrieved from the SciFinder-n (CAS) database in April 2026.

The hybrid organic–inorganic architecture of MOFs enables exceptional structural tunability through rational metal-linker selection and postsynthetic modification, allowing optimization of drug-loading efficiency, cargo release behavior, colloidal stability, biodegradability, and cellular internalization. To date, iron-based MOFs have been extensively investigated for biomedical applications due to their good biocompatibility, high in vivo tolerance (oral LD₅₀ ≈ 30 g kg^–1 in rats), and inherently high porosity, which facilitates efficient drug encapsulation. More recently, zirconium-based MOFs (Zr-MOFs) have emerged as an attractive alternative class of biocompatible carriers (Figure b). Zirconium is naturally present in trace amounts in the human body (∼300 mg) and has an established safe daily intake (∼3.5 mg). Although zirconium salts exhibit a lower oral LD₅₀ (∼4.1 g kg^–1 in rats) than iron-based compounds, their strong hard Lewis acid–base coordination with carboxylate linkers imparts superior chemical and mechanical stability, enabling extensive postsynthetic functionalization while maintaining high porosity and physiological stability.

Zr-MOFs offer several unique advantages that make them particularly well suited for stimuli-responsive drug delivery. , The hydrothermal stability of MOFs is largely governed by the metal–ligand bond strength, which depends on the nature of both the metal ion and the ligand. A defining characteristic of Zr­(IV) is its high oxidation state, leading to an elevated charge density and strong bond polarization. As a result, Zr­(IV) forms robust coordination interactions, giving rise to highly stable framework structures. According to Pearson’s hard–soft acid–base (HSAB) principle, Zr­(IV) (a hard acid) strongly binds to carboxylate oxygen atoms (hard bases), further contributing to the exceptional chemical and mechanical stability of Zr-MOFs. This strong coordination enables Zr-MOFs to remain stable under physiological conditions while still allowing controlled degradation under specific biological triggers. ,− Importantly, the hard Lewis acid nature of Zr⁴⁺ centers enables selective responsiveness to biologically relevant anions such as phosphate and ATP through competitive coordination interactions, providing a unique mechanism for programmable drug release. In addition, defect engineering and postsynthetic modification of Zr₆ clusters allow precise tuning of the pore environment, surface functionality, and degradation kinetics. Zirconium is also considered biologically safe, with low intrinsic toxicity, further supporting the biomedical applicability of Zr-MOFs. This combination of high structural robustness with tunable responsiveness distinguishes Zr-MOFs from many other MOF-based carriers and underpins their suitability for smart cancer nanomedicine design.

Despite the rapid expansion of research on Zr-MOF-based nanocarriers (Figure b), a comprehensive and design-oriented analysis of stimuli-responsive Zr-MOFs for targeted cancer drug delivery remains underexplored. Existing reviews predominantly provide broad overviews of Zr-MOFs, with emphasis on synthetic methodologies, surface functionalization, and general biomedical applications, rather than a systematic evaluation of endogenous- and exogenous-stimuli-responsive design principles. ,− For example, Forgan et al. comprehensively reviewed zirconium-based MOFs for drug delivery and biomedical applications, focusing on surface functionalization strategies, colloidal and hydrolytic stability, controlled cargo release, and in vitro/in vivo performance. Zhou et al. presented a broad overview of Zr-MOFs covering their design and synthesis, structural characteristics, and broad applications in catalysis, molecular adsorption/separation, drug delivery, fluorescence sensing, and as versatile porous carriers. Maleki et al. highlighted Zr-based nanozymes and their enzyme-mimicking activities and applications in biosensing, anticancer therapy, and antibacterial treatment. Those reviews primarily emphasized catalytic behavior rather than drug delivery system design. Wani et al. discussed Zr-MOFs as versatile and biocompatible nanoplatforms for theranostic applications, integrating bioimaging with controlled drug delivery for the treatment of cancer and AIDS. Maiti et al. systematically reviewed Zr-MOF synthesis methodologies and discussed their broad biorelated applications, encompassing drug delivery, anticancer activity, biosensing, and imaging technologies. Yazdian et al. conducted a detailed investigation of a representative Zr-MOF system, UiO-66 nanoparticles, focusing on their synthesis methods, biocompatibility, drug loading approaches, and controlled release properties as a drug delivery platform. However, a comprehensive and critical comparison of endogenous (pH, redox, enzyme, ATP) and exogenous (light, temperature, ultrasound) stimuli-responsive Zr-MOF designs for targeted cancer drug delivery remains limited. This review aims to fill this important gap by presenting a comprehensive, design-focused analysis of stimuli-responsive Zr-MOFs for targeted cancer therapy. The review classifies Zr-MOF systems according to their responsive triggers, elucidates structure-stimulus-function relationships across key framework families, and compares therapeutic outcomes across reported systems. Beyond summarizing current progress, this review offers forward-looking design principles to guide the development of next-generation, multistimuli-responsive Zr-MOF nanocarriers with enhanced selectivity, controlled release profiles, improved biodistribution, and strong translational promise for cancer nanomedicine.

2. Structural Types of Zr-MOFs for Cancer Drug Delivery

Zr-MOFs have attracted considerable attention in cancer drug delivery due to their outstanding chemical stability, favorable biocompatibility, and adaptable structural features. Several Zr-MOF families, including UiO, PCN, NU, MOF-808, and MOF-525, have been widely explored in cancer nanomedicine, collectively offering diverse pore architectures and therapeutic functionalities.

The zirconium-based MOF UiO-66 was first introduced in 2008 by Lillerudand coworkers, with “UiO” denoting the University of Oslo. UiO-66 features two distinct types of microporous cavities, namely tetrahedral and octahedral. Structurally, UiO-66 consists of 12-connected [Zr₆(μ₃-O)₄(μ₃-OH)₄(COO)₁₂] secondary building units (SBUs) linked by linear terephthalate (BDC) ligands, forming a highly stable framework with fcu topology (Figure a). Isoreticular expansion of UiO-66 with longer dicarboxylate linkers results in the formation of UiO-67 and UiO-68, which preserve the same Zr₆ cluster and framework topology while exhibiting increased pore dimensions. While UiO-66 offers superior framework stability and is well suited for small-molecule drug delivery, UiO-67 and UiO-68-constructed from biphenyl dicarboxylate and terphenyl dicarboxylate linkers, respectively, enable higher drug loading and accommodate bulkier therapeutics, photosensitizers, and biomacromolecules (Figure a). , In addition to their structural robustness, UiO-type Zr-MOFs are particularly well suited for pH-responsive drug delivery systems as protonation under acidic tumor conditions can weaken coordination bonds or host–guest interactions, enabling controlled release. Furthermore, their ease of surface functionalization allows integration of polymeric or biomolecular gatekeepers, facilitating enzyme-, ATP-, or redox-responsive designs.

2.

Representative organic linkers employed in the construction of major Zr-MOF families, including (a) UiO, PCN, and NU series. (b) Crystal structure-based packing diagrams of representative Zr-MOFs. Reproduced with permission. Copyright 2019, Elsevier.

The PCN (Porous Coordination Network) family has gained significant attention owing to its tetrakis­(4-carboxyphenyl)­porphyrin (TCPP) linker, which imparts intrinsic photophysical activity. The combination of porphyrinic linkers with chemically stable Zr₆ clusters allows PCN-type MOFs to function as multifunctional platforms for drug delivery, photodynamic therapy (PDT), photothermal therapy (PTT), and bioimaging, with additional versatility arising from metalation and postsynthetic modification. Notably, planar tetracarboxylate porphyrins coordinated with 12-connected Zr₆ SBUs form PCN-223, whereas coordination with 6-connected Zr₆ SBUs yields PCN-224 (Figure b), leading to distinct topologies and porosity that influence therapeutic performance. Owing to the presence of porphyrinic linkers, PCN-type Zr-MOFs are especially advantageous for light-responsive applications, including photodynamic and photothermal therapy. Their intrinsic photosensitizing capability enables ROS generation under light irradiation, making them ideal platforms for externally triggered drug release and multimodal cancer therapy.

The NU series, represented by NU-1000 and NU-901, is distinguished by large pore channels and a tunable framework connectivity. NU-1000, constructed using a pyrene-based tetratopic linker, provides mesoporous channels suitable for loading bulky drugs and biomolecules (Figure ). In contrast, NU-901 exhibits higher connectivity and improved structural robustness. , These complementary features make the NU series attractive for the controlled and sustained cancer drug delivery. The relatively large pore dimensions and high surface area of NU-series Zr-MOFs make them well suited for diffusion-governed drug release and integration of multiple functional entities. These features facilitate the development of multistimuli-responsive systems, where combinations of internal and external triggers can be integrated within a single platform.

Beyond these families, MOF-808 and MOF-525 further expand the Zr-MOF design space for cancer therapy. MOF-808, composed of Zr₆ clusters interconnected by 1,3,5-benzenetricarboxylate (BTC) linkers, features reduced connectivity and undergoes rapid degradation in the presence of phosphate ions, making it a promising candidate for ion-responsive and biodegradable chemotherapy delivery. , In contrast, MOF-525 is a porphyrinic Zr-MOF closely related to PCN-type structures and displays strong intrinsic photoactivity, highly suitable for theranostic and PDT applications. , Together, these representative Zr-MOF families highlight the remarkable versatility of zirconium-based frameworks in enabling diverse and advanced strategies for cancer drug delivery, ranging from small-molecule chemotherapy to photoresponsive and theranostic nanomedicine. Notably, MOF-808 is highly responsive to phosphate ions due to its lower connectivity and susceptibility to competitive coordination, enabling ion-triggered degradation and drug release. In contrast, MOF-525, with its porphyrinic structure, is particularly suited for light-responsive therapeutic applications.

3. Biocompatibility of Zr-MOFs

Biocompatibility is a key factor for the successful application of MOFs in biomedical fields. Among the different metal nodes explored, zirconium stands out as a highly suitable choice due to its low intrinsic toxicity, chemical stability, and good tolerance under physiological conditions. , Zirconium is naturally present in the human body in trace amounts, and toxicological studies have shown that common zirconium salts exhibit relatively high in vivo tolerance, supporting the general safety of Zr-based materials. Importantly, metal ion toxicity is closely associated with bioaccumulation; unlike many heavy metals, zirconium can be efficiently eliminated from biological systems, contributing to its favorable biocompatibility profile. Consistent with this, the oral LD₅₀ of zirconyl acetate in rats has been reported to be approximately 4.1 g kg^–1, comparable to values observed for other metals widely employed in biomedical materials.

The effectiveness of a drug delivery system largely depends on its capacity to cross the cell membrane and transport therapeutic agents to intracellular targets. Efficient cellular uptake, favorable internalization pathways, and minimal intrinsic cytotoxicity are critical determinants of successful drug delivery. Accordingly, in vitro assays such as MTT and MTS are commonly used as preliminary screening methods to assess how particle size, surface modification, and drug loading affect cellular responses. However, direct comparison of cytotoxicity data across different studies should be approached with caution, as measured IC₅₀ values are highly sensitive to experimental parameters, including assay type, exposure duration, surface chemistry, and cell passage history, particularly for genetically unstable cell lines such as HeLa. In this context, reported IC₅₀ values for UiO-66 nanoparticles against HeLa cells show significant variation, ranging from 1.50 ± 0.15 mg mL^–1 (261 ± 12 nm, HCl-modulated, MTS assay, 24 h) to 0.40 ± 0.01 mg mL^–1 (100 ± 20 nm, HCl-modulated, MTT assay, 24 h) and exceeding 1 mg mL^–1 (77 ± 24 nm, DCA-modulated, MTS assay, 72 h). − Importantly, IC₅₀ values in this range generally indicate low intrinsic cytotoxicity, suggesting that UiO-66 frameworks are largely biocompatible and suitable as drug delivery carriers, particularly at moderate doses. Nevertheless, these concentrations remain relatively high compared to those anticipated for clinical application. UiO-66, UiO-66-NH₂, and UiO-67 demonstrate good compatibility with MCF-7 breast cancer cells at concentrations up to 0.2 mg mL^–1. However, UiO-66-NH₂ shows enhanced cytotoxic effects toward HepG2 liver cancer cells at this concentration. Protonation increases the positive surface charge of the nanoparticles, promoting their cellular uptake through electrostatic attraction to the negatively charged cell membrane. The biocompatibility of Zr-MOFs has been systematically evaluated both prior to and following surface functionalization. In HEK293 human kidney cells, amine-functionalized UiO-66-NH-Q exhibited reduced cell viability at concentrations ≥25 μg mL^–1, whereas capping with Cp5 eliminated this effect, maintaining cell viability up to 50 μg mL^–1, highlighting the beneficial role of surface modification in mitigating cytotoxicity. ,

Overall, Zr-MOFs represent highly promising materials for biomedical applications due to their large surface area, structural robustness, tunable properties, and effective drug delivery performance. Nevertheless, successful clinical translation requires careful control of biocompatibility and toxicity. While zirconium itself exhibits low toxicity and organic linkers can be engineered for biological compatibility and degradability, factors such as surface chemistry, synthesis-related impurities, and the safety of degradation products must be rigorously evaluated. Accordingly, systematic in vitro and in vivo studies are essential to establish the long-term biosafety of Zr-MOFs for therapeutic use.

4. Stimuli-Activated Zr-MOFs for Targeted Cancer Therapy

The rational design of stimuli-responsive Zr-MOFs is central to their successful application in targeted cancer drug delivery (Figure ). The tumor microenvironment (TME), which represents the unique local environment surrounding cancer cells, is a key contributor to tumor progression, invasion, and metastatic spread. This environment exhibits multiple abnormal biochemical and physiological features, including acidic pH values, redox disequilibrium, elevated glycolytic metabolism, altered ion concentrations, and dysregulated enzyme expression (Figure ). Despite its inherent complexity, the TME offers exploitable endogenous signals that can be harnessed for the development of selective and effective anticancer therapies. , In parallel, the incorporation of externally applied physical stimuli-including light, temperature, and ultrasound into Zr-MOF drug delivery systems offers an additional level of spatiotemporal control over drug release and therapeutic activation (Figure ). In recent years, Zr-MOF-based strategies have been proposed to trigger drug delivery by capitalizing on this internal and external activation mechanism. Accordingly, stimulus-responsive smart nanoplatforms designed to respond to TME-derived signals as well as externally applied triggers, and multiple stimuli-responsive reports are summarized in Tables –, with representative examples discussed in detail in the following subsections. Such stimulus-mediated release mechanisms improve site-specific targeting and significantly reduce off-target toxicity. Furthermore, surface functionalization and ligand modification of Zr-MOFs facilitate selective interactions with biological systems, enabling tumor-specific accumulation and the modulation of cellular pathways.

3.

Schematic representation of drug-loaded Zr-MOFs responding to endogenous and exogenous stimuli for controlled drug release. Created with BioRender.com.

1. Endogenous-Stimuli-Responsive Zr-MOF for Cancer Nanomedicine.

MOF type	Drug name/loading (%)	Size (nm)/Surface Coating	Cell line/Invivo model	Stimuli	Release Mechanism	Ref
MOF-801	5-FU/88.5	40–80/NA	SW480/NA	pH	Diffusion-controlled
MOF-808	QU/43	193/Chitosan-FA	MCF-7/NA	pH	Diffusion-controlled
MOF-808	5-FU/36.9	200/Polydopamine	MCF-7/NA	pH	Gating
MOF-808 & NH2–UiO-66	5-FU/38 and 30%	100/FA	HeLa/NA	pH	Diffusion-controlled
UiO-66	5-FU/NA	40–80/Chitosan-lysine polymer	MCF-7, Caco-2/NA	pH	Swelling-controlled
UiO-66-NH2	5-FU/30%	145/Histidine	U87MG glioblastoma/NA	pH	Diffusion-controlled
UiO-67-NH2	5-FU & PMT/6.5 and 18.5	200/FA	A549, HeLa, KB/mice	pH	Framework degradation
UiO-66	Cisplatin & Cyclophosphamide/74.2 and 61.9	233/FA-PEG	SKBR3, 4T1/NA	pH	Framework degradation
Fe3O4–COOH@UiO-66-NH2	Quercetin/43.1	140/NA	MDA-MB-231/NA	pH	Framework degradation
UiO-67	Gefitinib/23.8	<100 nm/NA	HeLa/NA	pH	Framework degradation
UiO-66-NH2	Dox/∼12.6%	100/NA	MNNG/HOS, MDA-MB-231, MNNG/mice	pH	Bond disruption
MOF-808	Carboplatin/4.5	85/galactose	HepG2, MIA PaCa-2, 2D and 3D spheroids/NA	Phosphate ion	Competitive coordination
Zr-MOF/Fumaric acid	DCA/20	168/PEG & FA	HeLa, MCF-7/NA	Phosphate ion	Competitive coordination
UiO-66	Cisplatin/25.7	50/NA	NA	Phosphate ion	Competitive coordination
NU-1000	Dox/35	100/PEG	HeLa/mice	Phosphate ion	Framework degradation
NU-901	Pemetrexed/25	200/asolectin & Pluronic F-127	A549, MSTO-211H/NA	Phosphate ion	Diffusion-controlled
PCN-224	Dox/108	90/HA	MDA-MB-231, SCC-7 MCF-7/NA	Enzyme	Gating
UiO-68	CPT/61 μmol g–1	100–150/DNase I	MDA-MB-231/NA	Enzyme	Gating
UiO	Dox/46.5 nmol mg–1	200–250/ATP-AS1411 hybrid aptamer	MDA-MB-231/NA	ATP	Gating
MOF-801	CpG ODNs & DMXAA/8.3 and 1.5	NA/CpG oligonucleotides	RAW264.7 μBDCs, Hepa1–6/mouse	ATP	Competitive coordination
UiO-67	Curcumin/11.8	169/NA	HeLa, MDA-MB-231/mice	GSH	Framework degradation
UiO-66	Cisplatin, CPT, & Dox/NA	NA/Polymer shell (PAC, PAA, & PEG)	U87MG, A431/mice	GSH	Gating

3. Multiple-Stimuli-Responsive Zr-MOFs for Cancer Nanomedicine.

MOF Type	Drug name/Drug loading (%)	Size (nm)/Surface coating	Cell line/Invivo model	Stimulus	Release Mechanism	Ref
PCN-224	-	280/MnO2 shell	MCF-7/mice	pH, GSH, & H2O2	Framework degradation
UiO	Dox/NA	250–300/DNAzyme & ATP aptamer	MDA-MB-231/NA	pH, metal-ion, & ATP	Gating
Au-PCN-223(Fe)	-	70/NA	4T1/mice	Glucose, H2O2, & pH	ROS generation
Fe-doped MOF-808	Carboplatin/6	∼50/PEG	HepG2, HepG2 3D tumor spheroids	Phosphate & H2O2	Framework degradation
UiO-67	Dox/0.23 mmol g–1	195/Cyclodextrin polymer	HeLa/mice	pH and enzyme	Gating
UiO-66	DOX/28	190–200/Polydopamine & Transferrin	4T1/Wistar rats	pH and light (808 nm)	Outer coating destabilization
MOF-808	IR 780/35	148/Catalase	HeLa/NA	Light (808 nm), pH, enzyme & H2O2	Surface dissociation
PCN-224	CPT & Dox/NA	240/Silane, DNA & ZIF-8 film	SK-BR-3/mice	pH, enzyme and light (660 nm)	Gating
PCN-224	-	120/DNA	A549, HeLa/mice	Enzyme, light	Gating

4.1. Stimulation by Internal Microenvironment

4.1.1. pH-Responsive

TME is mildly acidic as a result of hypoxia-induced metabolic alterations, enhanced glycolytic activity, and the buildup of lactic acid during rapid tumor proliferation. As a consequence, the extracellular pH in tumor tissues generally falls within the range of 6.0–7.0, compared to the near-neutral pH (∼7.4) observed in normal tissues and blood. Following cellular internalization, nanocarriers encounter highly acidic intracellular compartments, including endosomes and lysosomes, where the pH typically drops to 4.0–6.0. − Exploiting these pH gradients, acid-responsive Zr-MOFs have been developed for targeted drug delivery. − These systems enable controlled cargo release through mechanisms including protonation-induced disruption of coordination bonds, cleavage of acid-labile linkages, activation of pH-sensitive components, and weakening of host–guest interactions. Protonation of organic linkers or functional groups under acidic conditions can induce partial framework destabilization or gatekeeper removal, thereby facilitating site-specific drug release. As a result, pH-responsive Zr-MOF platforms have emerged as promising candidates for cancer therapy, offering enhanced therapeutic efficacy while minimizing off-target toxicity. Table summarizes reported pH-responsive Zr-MOFs for targeted cancer drug delivery. The pH-responsive behavior of Zr-MOFs is mainly attributed to protonation-induced weakening of coordination interactions between Zr₆ clusters and organic linkers or encapsulated molecules, along with the disruption of host–guest interactions in acidic environments. In some systems, this leads to partial framework degradation, while in others, it results in enhanced diffusion or swelling, depending on the surface modification and structural stability (Table ).

Primarily, pH-responsive Zr-MOF-derived drug delivery systems relied on intrinsic framework destabilization under acidic conditions. Akhbari et al. reported that MOF-801 functions as a biocompatible and effective pH-responsive carrier for 5-fluorouracil (5-FU), showing significantly enhanced drug release at pH 5.0 compared to physiological conditions, attributed to partial framework degradation and weakened host–guest interactions. This system exhibited increased cytotoxic effects against SW480 colon cancer cells, while maintaining minimal toxicity toward HEK-293 normal cells, highlighting its tumor-selective therapeutic potential. Akhbari’s group also reported MOF-808 loaded with quercetin (QU) at a high loading capacity (∼43%), followed by surface decoration with a folic acid (FA)-conjugated chitosan (QU@MOF-808@CS-FA), where acidic conditions promoted rapid drug release (Figure a). Similarly, defect-engineered polydopamine-coated MOF-808 developed by Goddard et al. exhibited accelerated 5-FU release at pH 5.5, highlighting how reduced cluster connectivity enhances pH sensitivity while retaining sufficient stability under physiological conditions.

4.

Schematic illustration of pH-responsive drug release mechanisms in the Zr-MOF system. (a) Schematic of the synthesis of QU@MOF-808@CS-FA and its working principle of pH-responsive QU release from QU@MOF-808@CS-FA. Reproduced with permission. Copyright 2022, ACS. (b) Schematic representation of the preparation of the coloaded system 5-FU/UiO-67-(NH)₂-FAM/PMT and its proposed mechanism for cancer therapy. Reproduced with permission. Copyright 2021, Elsevier.

To enhance colloidal stability and prevent premature drug release, polymeric or ligand-based gatekeeping strategies have been extensively incorporated into Zr-MOF systems. Chitosan, polydopamine, and PEG-based coatings not only enhance biocompatibility but also introduce additional pH sensitivity through protonation-induced swelling or dissociation. − For example, Zhang et al. similarly anchored folic acid directly onto surface Zr₆ clusters of MOF-808 and NH₂–UiO-66, enabling receptor-mediated uptake and accelerated drug 5-FU release under mildly acidic conditions without complete framework collapse. These studies demonstrate that surface coordination to Zr₆ nodes offers a robust and modular strategy for combining pH responsiveness with active targeting. UiO-66-based systems, although intrinsically more stable, can also exhibit pH responsiveness through surface modification. Sheta et al. described a chitosan–l-lysine-coated UiO-66 system that showed minimal drug release at pH 7.4 but significantly accelerated release at pH 5.5, leading to apoptosis-driven cell death in MCF-7 and Caco-2 cancer cells. Huntošová et al. further introduced histidine-functionalized UiO-66-NH₂, where imidazole groups acted as pH-sensitive moieties to trigger drug release under mildly acidic conditions, achieving efficient cytotoxicity in U87MG glioblastoma cells, including 3D spheroid models.

Beyond single-drug pH-responsive carriers, UiO-type Zr-MOFs have been developed as multifunctional platforms that integrate pH-triggered release with combination therapy, active targeting, and imaging. Liu et al. developed a multifunctional aminated UiO-67 platform for synergistic cancer therapy through a bimodal drug delivery approach (Figure b). This work presents the development of a multifunctional UiO-67-NH₂ nanoplatform (5-FU/UiO-67-(NH)₂-FAM/PMT) capable of codelivering two chemotherapeutic agents, 5-FU and pemetrexed (PMT), while also providing folate receptor-targeted delivery and fluorescence imaging functionality. To introduce fluorescence imaging capability, the amino-functionalized framework was conjugated with 5-carboxyfluorescein. Yaraki et al. engineered folic acid-PEG modified UiO-66 MOF as a targeted and pH-responsive nanocarrier for the codelivery of cisplatin and cyclophosphamide in breast cancer therapy. Core–shell architectures incorporating magnetic nanoparticles have also been explored to introduce multifunctionality. Akhbari et al. reported Fe₃O₄@UiO-66-NH₂ systems for quercetin delivery, where acidic pH triggered accelerated drug release, while the magnetic core enabled potential magnetic targeting. These hybrid systems demonstrated selective cytotoxicity toward breast cancer cells with good biocompatibility with normal cells. Related UiO-67 and UiO-66-NH₂ systems further demonstrate the potential of Zr-MOFs for tumor-selective chemotherapy and tissue-support functions. ,

4.1.2. Ion-Responsive

Ion-responsive MOFs represent an emerging class of smart nanocarriers for biomedical applications, particularly controlled cancer drug delivery. These systems are engineered to respond to specific inorganic ions in physiological environments through processes such as structural reorganization, ligand exchange, and partial framework degradation. Strong electrostatic interactions between charged therapeutic agents and metal nodes enable high drug loading efficiency, while competitive interactions with endogenous ions, especially phosphate, can trigger cargo release through ion-exchange processes. In ion-responsive Zr-MOFs, drug release is predominantly governed by competitive coordination chemistry, wherein biologically abundant ions with a higher binding affinity displace weaker metal–ligand interactions within the framework. This mechanism is particularly relevant for Zr-MOFs, as Zr⁴⁺ centers exhibit strong hard Lewis acid character and preferentially coordinate to hard base anions such as phosphate. Although most MOFs are overall neutral in charge, rational selection of metal clusters and ligands can impart sensitivity toward biologically relevant ions such as phosphate, Mg²⁺, Ca²⁺, Zn²⁺, and K⁺. Among the various mechanisms reported, competitive coordination, where ions with stronger binding affinity replace weaker metal–ligand interactions, plays a key role in enabling controlled drug release in pathological microenvironments. Table summarizes representative ion-responsive Zr-MOF systems for targeted cancer therapy. Ion-responsive behavior in Zr-MOFs is predominantly governed by competitive coordination mechanisms, where biologically abundant ions such as phosphate exhibit stronger binding affinity toward Zr⁴⁺ centers, thereby displacing coordinated ligands or disrupting the framework structure, ultimately triggering controlled drug release (Table ).

Exploiting phosphate-responsive competitive coordination, Forgan et al. developed a MOF-808 nanoplatform for targeted chemotherapy by encapsulating carboplatin and introducing galactose for receptor-mediated uptake. The strong affinity of phosphate ions for Zr₆ clusters induced partial framework disassembly, triggering drug release, while galactose functionalization enhanced selective uptake by asialoglycoprotein receptor-overexpressing cancer cells, leading to improved cytotoxicity in both 2D and 3D tumor models with minimal toxicity to normal cells. In related work, nanoscale Zr-fumarate (Zr-fum) MOFs loaded with dichloroacetate show enhanced cancer cell internalization with reduced macrophage uptake, while PEG or folic acid modification improved colloidal stability, immune compatibility, and selective cytotoxicity. Phosphate-triggered degradation under physiological conditions facilitates controlled drug release, establishing Zr-fum as a biocompatible and mechanistically robust Zr-MOF platform for cancer nanomedicine. Lin et al. reported a defect-engineered UiO-66 platform enabling exceptionally high loading of a cisplatin prodrug via phosphonoacetate anchoring to Zr₆ clusters. In phosphate-containing media, competitive coordination induced rapid framework degradation and burst drug release, establishing a mechanistically relevant phosphate-responsive design, despite the absence of biological validation. Similarly, Lin et al. developed NU-1000 nanoparticles as biodegradable Zr-MOF carriers for doxorubicin (Dox) delivery, where phosphate-triggered degradation facilitated sustained drug release, efficient cellular uptake, and notable tumor suppression in vivo with minimal systemic toxicity. In contrast, Stefan and his team demonstrated that coating NU-901 MOF nanoparticles with a lipid-polymer bilayer suppresses rapid phosphate-induced degradation, shifting drug release toward a diffusion-dominated mechanism. This stability-engineered strategy highlights an alternative approach to mitigating premature framework collapse under physiological conditions.

4.1.3. Enzyme-Responsive

Highly specific catalytic enzymes play a vital role in sustaining normal physiological activities and metabolic homeostasis. However, cancer initiation and progression are frequently associated with the aberrant upregulation or overexpression of certain enzymes within the TME. , These enzymatic alterations serve as effective endogenous triggers for the rational design of enzyme-responsive Zr-MOF systems in targeted cancer drug delivery. − In this context, Zr-MOFs provide distinct advantages due to their modular surface chemistry, coordinatively unsaturated Zr₆ clusters, and structural robustness, which allow enzyme-triggered ligand cleavage, gatekeeper removal, or framework transformation to be precisely engineered. , Accordingly, this section highlights representative tumor-overexpressed enzymes and recent advances in enzyme-responsive Zr-MOF platforms for targeted cancer therapy, where Table summarizes reported enzyme-triggered Zr-MOFs for targeted cancer drug delivery.

Hyaluronidase is commonly overexpressed in a wide range of tumors and plays a critical role in extracellular matrix remodeling, making it an attractive trigger for enzyme-responsive nanomedicine. Ryu et al. developed a hyaluronic acid (HA)-coated, enzyme-responsive Zr-MOF nanoplatform based on the porphyrinic framework PCN-224 for targeted cancer therapy (Figure a). Dox was physically encapsulated within the porous PCN-224 framework, while HA was coordinated to surface Zr₆ clusters, functioning as a polymeric gatekeeper to suppress premature drug leakage. The HA coating simultaneously enabled CD44-mediated cancer cell targeting and served as a hyaluronidase-cleavable barrier. Upon the enzymatic degradation of HA in tumor cells, intracellular drug release was triggered. Notably, the porphyrinic linker of PCN-224 acted as an intrinsic photosensitizer, generating singlet oxygen under light irradiation. This dual functionality enabled synergistic chemotherapy and PDT, resulting in significantly enhanced anticancer efficacy, including activity against multidrug-resistant cancer cells. This work highlights how enzyme-responsive gating can be combined with intrinsic MOF photophysics to achieve multimodal cancer therapy.

5.

(a) Illustration of the preparation of HA gatekeeper PCN-224 for chemotherapy and PDT. Created with BioRender.com. (b) Schematic illustration of the synthesis of nucleic acid–functionalized UiO-68 NMOFs, their cargo loading, and subsequent capping via hybridization between strand I′ and I-modified NMOFs to form duplex gatekeeping units. Reproduced with permission. Copyright 2019, Wiley-VCH.

Complementing this approach, Wilner et al. developed enzyme-responsive UiO-68 Zr-MOF nanoparticles by capping drug-loaded pores with sequence-specific nucleic acid duplexes (Figure b). The porous UiO-68 framework was loaded with CPT or fluorescent model cargos, and the pore openings were blocked using DNA gates that could be selectively cleaved by specific enzymes, including DNase I, Exonuclease III (Exo III), EcoRI, or nicking enzymes. Importantly, an ATP-assisted Exo III system facilitated selective intracellular activation in cancer cells, resulting in enhanced cytotoxicity toward MDA-MB-231 breast cancer cells while minimizing effects on normal MCF-10A cells. This study elegantly demonstrates how enzymatic specificity can be leveraged to achieve cancer-selective drug release using Zr-MOF platforms.

4.1.4. ATP-Responsive

Adenosine triphosphate (ATP) functions as the main energy carrier in living systems with energy released through the hydrolysis of its phosphoanhydride bonds. Elevated ATP levels are commonly observed in various pathological conditions, including chemoresistance, uncontrolled tumor growth, and disrupted neuronal signaling, thereby making ATP a valuable biomarker for differentiating cancer cells from normal tissues. Driven by these findings, a variety of ATP-responsive drug delivery systems have been developed that utilize ATP recognition mechanisms, frequently employing ATP-specific aptamers to achieve competitive binding-induced cargo release (Table ).

A representative aptamer-gated approach was demonstrated by Willner et al., who developed an ATP-responsive Zr-MOF nanoplatform by functionalizing the nanoparticles with nucleic acid gatekeepers incorporating ATP-specific aptamer sequences. The MOF pores were loaded with a fluorescent probe and the anticancer drug Dox, followed by capping through duplex formation between anti-ATP aptamer sequences and complementary DNA strands (Figure a). In ATP-rich cancer cells, competitive binding between ATP and the aptamer induces gate opening and triggers cargo release. Moreover, integration of a nucleolin-targeting AS1411 aptamer significantly enhanced cancer cell selectivity, leading to increased tumor uptake and cytotoxicity in breast cancer cells while maintaining minimal toxicity toward normal cells. This work exemplifies how ATP-responsive aptamer gating can leverage intracellular metabolic differences to achieve highly selective Zr-MOF-based drug delivery. Beyond nucleic acid recognition, ATP responsiveness can also be achieved through competitive coordination interactions with Zr₆ clusters. Liu et al. reported an ATP-responsive MOF-801-based immunotherapeutic nanoplatform for cancer immunotherapy, in which CpG oligonucleotides and the STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) were codelivered via coordination to Zr₆ nodes. Elevated intracellular ATP levels in tumor tissues competitively bound to Zr⁴⁺ centers, inducing partial framework disruption and controlled release of the immunomodulators. Remarkably, MOF-801 itself exhibited intrinsic STING agonist activity, synergistically reprogramming tumor-associated macrophages, promoting dendritic cell maturation, and suppressing tumor angiogenesis. In hepatocellular carcinoma models, this ATP-responsive system elicited robust systemic antitumor immunity, resulting in effective tumor eradication and prevention of recurrence with minimal systemic toxicity. These complementary approaches position ATP-responsive Zr-MOFs as powerful platforms for intracellularly activated chemotherapy and immunotherapy.

6.

(a) Schematic depicting DNA-modified Zr-MOFs containing drug cargo, where loading is secured by DNA–aptamer duplex formation, and release occurs through ATP-induced duplex dissociation. Adapted with permission. Copyright 2017, Wiley-VCH. Created with BioRender.com. (b) Schematic illustration of the synthesis of CCM@MOF-M­(DTBA) and its redox-responsive degradation behavior in tumor environments. Reproduced with permission. Copyright 2018, ACS.

4.1.5. Redox-Responsive (GSH-Triggered)

Redox-responsive MOFs utilize the differential redox environment between tumor tissues and normal cells to enable selective intracellular drug release. Cancer cells are recognized by abnormally high concentrations of reduced glutathione (GSH), a potent intracellular reductant capable of cleaving redox-labile bonds, such as disulfide linkages. Incorporation of these GSH-sensitive motifs into Zr-MOFs or surface coatings enables tumor-specific degradation or structural transformation, thereby promoting preferential drug release within cancer cells while limiting off-target toxicity.

In this context, He et al. developed an intrinsically redox-responsive CCM@MOF-M­(DTBA) system by integrating a disulfide-containing organic linker into the framework. Elevated intracellular GSH levels triggered the cleavage of the disulfide bonds, leading to framework degradation and controlled release of the encapsulated anticancer drug curcumin (Figure b). The system demonstrated enhanced cytotoxicity in vitro and significant tumor growth inhibition in vivo, highlighting the potential of intrinsically GSH-responsive Zr-MOFs for tumor-selective chemotherapy. Complementing intrinsic framework responsiveness, surface-engineered strategies have been employed to balance redox sensitivity with physiological stability. Chen et al. addressed the limited stability of UiO-66 in phosphate-rich biological environments by introducing a disulfide-cross-linked polymer shell through in situ surface polymerization. The polymer coating protected the MOF from premature phosphate-induced degradation during circulation while enabling GSH-triggered intracellular activation. Upon cellular uptake, reduction of the disulfide cross-links exposed the MOF core to intracellular phosphate ions, resulting in controlled release of multiple anticancer agents, including cisplatin, CPT, and Dox. This polymer-protected and redox-activated strategy led to prolonged blood circulation, enhanced tumor accumulation, and improved therapeutic efficacy in vivo. Collectively, GSH-triggered Zr-MOFs demonstrate that redox-responsive drug delivery can be achieved either through the intrinsic incorporation of redox-labile linkers or through surface-engineered protective layers that couple redox activation with controlled framework exposure. Future redox-responsive Zr-MOF designs should emphasize the precise tuning of redox sensitivity and structural stability to maximize tumor selectivity while preserving favorable pharmacokinetics.

4.2. Stimulation by External Energy Fields

TME-responsive Zr-MOFs facilitate selective cancer drug delivery by leveraging endogenous stimuli, including pH variations, ionic conditions, redox imbalances, ATP levels, and enzyme overexpression. However, drug release relying solely on intrinsic TME stimuli is often challenging to precisely control, as activation occurs automatically upon exposure to the relevant trigger, offering limited external regulation after systemic administration. In contrast, the integration of externally applied physical stimuli-including light, temperature, and ultrasound into Zr-MOF drug delivery systems offers an additional level of spatiotemporal control over drug release and therapeutic activation (Figure ). Although the application of external stimuli such as light and heat may be restricted by factors, including limited tissue penetration, their integration into cancer therapy can significantly accelerate Fenton and Fenton-like reactions. More importantly, externally applied physical triggers enable spatiotemporal modulation of therapeutic responses, thereby enhancing ROS generation and improving the overall treatment efficacy.

A variety of external stimuli have been explored to enhance drug delivery performance, including light irradiation, thermal stimulation, and ultrasound activation. − ,,− Among these, near-infrared (NIR) light has attracted considerable attention owing to its relatively deep tissue penetration, low phototoxicity, and excellent compatibility with PDT, PTT, and imaging-guided treatment modalities. Thermal and ultrasound stimuli further expand the toolbox of external activation strategies, offering complementary mechanisms for improving drug release kinetics, increasing tumor permeability, or enhancing catalytic activity within tumor tissues. ,− Zr-MOFs are highly suitable for externally triggered applications due to their robust structural stability, adjustable porosity, and adaptable surface chemistry. By rationally integrating exogenous responsiveness with intrinsic TME sensitivity within a single Zr-MOF platform, synergistic enhancement of targeting precision, drug release controllability, and therapeutic efficacy can be achieved. Such dual-responsive strategies represent a powerful and flexible approach for advancing the Zr-MOF-based nanomedicine in targeted cancer drug delivery. External stimuli-responsive Zr-MOF systems are summarized in Table .

2. Exogenous-Stimuli-Responsive Zr-MOFs for Cancer Nanomedicine.

MOF Type	Drug name/Loading (%)	Size (nm)/Surface coating	Cell line/Invivo model	Stimuli	Release Mechanism	Ref
PCN-224	-	180/HA	4T1, MCF-7/mouse	Light (650 nm)	Framework degradation
PCN-224	-	120/NA	MCF-7/NA	Light (1064 nm)	ROS generation
PCN-224	CORM-401/1.02	96/HA	RAW267.4/4T1	Light (660 nm)	ROS/CO generation
PCN-224	CPT/88	390/GST-Afb	SK-BR-3, 4T1/mouse	Light (650 nm)	Diffusion-controlled
MOF-525	-	197/HA	HepG2/NA	Light (800 nm)	ROS generation
MOF-525	-	<200/HA	HepG2/NA	Light (960 nm)	ROS generation
UiO-66	Geldanamycin/5.4	180/PNIPAAm	HepG2/mice	Light (808 nm)	Gating
UiO-67	Ru(bpy)3 2+ /13.85	92 nm/NA	A549/NA	Light (880 nm)	ROS generation
UiO-67 BPDC	CO/NA	90/PEG	MDA-MB-231/NA	Light (473 nm)	CO generation
UiO-68 TPDC-NH2	e6 & RB/ 10.2 & 10.5	216/PEG	4T1/mice	Light (880 nm)	ROS generation
69-L2 DPDB	-	171/F-PEG	MDA-MB-231/NA	Light (525 nm)	ROS generation
MOF-808	Gd-DTPA/27.4	110/PANI	4T1/mice	Light (808 nm)/heat	Heat generation
MOF-808	IR780	50/IgG	HeLa, 4T1/mice	Light (808 nm)	ROS generation
MOF-808	CPT & IR 780/83	110/GST-Afb, collagenase	SK-BR-3, 4T1/mice	Light (808 nm)	Diffusion-controlled
Zr-MOF (Fe)	Dox/92	34/Dex & RGD	B16F0/C57BL/6- mice	Light (808 nm)	Protonation-induced diffusion
Zr-MOF	-	265/NA	MCF-7/mice	Light (635 nm)	ROS generation
NU-901	Calcein & α-CHC/38 and 81	200/NA	HeLa	Thermal	Framework degradation
Mn-PCN-224	-	110/Pluronic F127	A549/mice	Ultrasound	ROS generation
Pt-PCN-224 (Fe)	-	272/COOH-PEG	C6 glioma cells/mice	Ultrasound	ROS generation
PCN-224	-	130/NA	CT26/mice	Ultrasound	ROS generation

4.2.1. Light-Responsive

PDT has gained attention as a minimally invasive cancer treatment approach, offering precise spatiotemporal control and lower systemic toxicity compared to conventional chemotherapy and radiotherapy. However, its clinical performance is often limited by the poor solubility and aggregation of photosensitizers, along with oxygen deficiency and redox imbalance in the hypoxic tumor microenvironment, which together reduce reactive oxygen species (ROS) generation under light irradiation. , Zr-MOFs provide a robust and highly tunable platform to address these limitations by enabling precise integration of photoactive ligands, high loading of therapeutic cargos, and versatile post-synthetic modification for biological optimization. In particular, BODIPY- and porphyrin-based Zr-MOFs have shown that rational control over framework architecture and surface engineering (e.g., PEGylation, fluorinated oxygen carriers, or redox-modulating shells) can enhance colloidal stability, improve oxygen transport, and significantly boost PDT performance in hypoxic solid tumors. − As summarized in Table , porphyrinic frameworks such as PCN-224 and MOF-525, UiO-type architectures (UiO-66/67/68), MOF-808, BODIPY-based 69-L2, and hybrid Fe-TCPP/TCPP systems integrate chemotherapeutics, imaging agents, and polymeric or biomolecular shells (e.g., HA, PEG, PNIPAAm, antibodies, fluorinated PEG) to achieve ligand- and coating-dependent control over light-triggered drug release, PDT/PTT effects, and tumor targeting across diverse cancer models. Within this landscape, BODIPY- and porphyrin-containing Zr-MOFs are particularly attractive, as their conjugated chromophores provide strong absorption in the visible to NIR region and high photosensitizer density, enabling efficient ROS generation that can be further amplified by microenvironment-responsive or oxygen-enriching components.

PCN-224, composed of Zr⁴⁺ clusters and tetrakis­(4-carboxyphenyl)­porphyrin (TCPP) linkers, functions as a porphyrin-based photosensitizing framework, offering high surface area, porous architecture, and efficient singlet oxygen (¹O₂) generation under ∼650 nm light irradiation. Shi et al. establish PCN-224 as a PDT core that can be combined with an inorganic nanozyme (Co₃O₄) and a simple targeting ligand (HA) to modulate the chemical TME (O₂/H₂O₂) and add CDT. Building directly on this concept of PCN-224 as an inorganic–organic ROS platform, Zeng et al. deepen the nanozyme–MOF integration by moving to bimetallic Pt/Pd nanozymes on PCN-224, thereby coupling CAT/POD-like catalysis with NIR-II photothermal heating and using it as a rigid catalytic/photothermal hub for maximized ROS generation. Extending the role of PCN-224 beyond hypoxia and H₂O₂ regulation in tumor cells, Liu et al. transform the same Zr-TCPP framework into an immune-metabolic nanoreactor by encapsulating a CO-releasing molecule (CORM-401) and wrapping the MOF in HA/TPP polymers, thus redeploying PCN-224 as a ROS/CO-driven platform for TAM killing and repolarization via glutamine/GSH metabolism in the TME. Addressing a key translational bottleneck common to these catalytic and immunomodulatory PCN-224 systems, our group then resolves the uncontrolled bionano interface by introducing a GST-affibody precoating that forms an orientation-controlled protein shield on the same Zr–TCPP core, preventing nonspecific corona formation, preserving HER2/EGFR-targeting, and still allowing PDT and drug loading, a surface strategy to endow catalytically and immunologically optimized PCN-224 platforms with stable, programmable targeting in vivo (Figure ).

7.

Schematic illustration of protein-corona-shielded PCN-224 (PCN) nanoparticles designed for targeted nanomedicine applications. The bare surface of PCN particles (i) is initially coated with GST-Afb protein (ii), which functions as a protective layer, preventing nonspecific serum protein adsorption until the particles reach Afb-targeted sites (iii). The resulting therapeutic effect arises from the combined action of the preloaded chemotherapeutic agent within the particles and the singlet oxygen generated by the porphyrin units of the PCN framework upon light irradiation. Reproduced with permission. Copyright 2023, Wiley-VCH.

Similarly, MOF-525 is a Zr₆-porphyrin (TCPP) framework that serves as a multifunctional porphyrinic core capable of visible/NIR-excited ¹O₂ generation, while its large pore system hosts additional functional components. Lee et al. embed Pd nanocubes into MOF-525 and wrap the composite with HA (Pd@MOF-525-HA) so that the porphyrinic lattice acts as a dual PDT/SDT sonosensitizer and two-photon fluorophore, whereas Pd catalyzes H₂O₂ to O₂ and •OH via a Fenton-like reaction, relieving hypoxia and adding CDT under light/ultrasound. Li et al. instead confine in situ polymerization of pyrrole inside MOF-525 to obtain PPyMOF-525-HA, in which the PPy phase provides high-efficiency NIR photothermal conversion (≈62%), while the porphyrin ligand still yields ¹O₂ under visible light, giving a HA-targeted nanoplatform that integrates fluorescence imaging, PDT, and strong PTT within a size-controlled, colloidally stable MOF-polymer hybrid.

UiO-66, UiO-67, and UiO-68 are all based on Zr₆ cluster frameworks; however, progressive elongation of the organic linkerfrom terephthalate (UiO-66) to biphenyl-4,4′-dicarboxylate (UiO-67) and triphenyl-based TPDC (UiO-68-NH₂)transforms these systems from relatively compact structures into more open architectures capable of accommodating advanced phototherapeutic functions. Zhou et al. use UiO-66-NH₂ as a compact nanoheater core to confine ultrasmall Pt nanozymes and graft a PNIPAAm shell plus GA, building a light-triggered cascade system where NIR-driven photothermal conversion in the Pt-loaded UiO-66 induces polymer collapse and synchronous HSP90 inhibition, thereby sensitizing tumor cells to hyperthermia in vitro and in vivo. In contrast, the larger-pore UiO-67 scaffold is exploited in two very different ways: Lee’s early work grafts π-conjugated ligands on UiO-67 to create a stable, strongly absorbing light-harvesting platform, e.g., for photocatalysis, while Hong et al. later dope UiO-67 with Co and Ru to obtain a CO₂-to-CO photocatalytic “gas nanoreactor” that, once PEGylated and F3-targeted, modulates hypoxia and synergizes with tirapazamine for CO-aided chemotherapy in triple-negative breast cancer. Pushing the same design logic to an even longer linker, Tian et al. leverage UiO-68-NH₂’s expanded mesopores to coload two photosensitizers (Ce6/RB) and electrostatically assemble multiple Nd-sensitized UCNPs onto each MOF core, creating a core–satellite UiO-68-UCNP superstructure with high dual-PS loading, efficient 808 nm-driven UCL-to-PS energy transfer, strong ROS production, and trimodal MR/UCL/FL imaging that overcomes overheating and shallow penetration limitations of conventional PDT.

Moreover, Jimenez et al. developed 69-L2, a BODIPY-based Zr-MOF made by single-crystal ligand exchange and then PEGylated (69-L2@F) to act simultaneously as an oxygen carrier and photosensitizer, enabling hypoxia-relieved, highly effective PDT against triple-negative breast cancer in vitro and in vivo. Similarly, Yang et al. employed MOF-808 as a Zr₆–BTC-based nanoplatform to spatially confine Gd-DTPA within its pores, followed by polyaniline surface coating to construct Gd-DTPA-MOF-808@PANI, which exhibited significantly enhanced r₁ relaxivity and strong photothermal conversion under 808 nm irradiation for MRI-guided in vivo photothermal therapy. Ryu et al. then repurposed the same MOF-808 scaffold as a biointerface-engineered drug carrier by precoating its surface with IgG (and then specific antibodies such as anti-EGFR/HER2/CD44), showing that supramolecular antibody conjugation occupies defect sites, suppresses protein corona formation, provides a stealth effect against macrophages, and yields plug-and-play, antibody-targeted MOF-808 nanoplatforms that deliver IR-780 for potent, receptor-selective PDT in 4T1 tumors (Figure ). Ryu et al. further reported a multifunctional, protein-precoated MOF-808 nanoplatform, where chemotherapeutic agents (CPT) or a photosensitizer (IR-780) were initially loaded into the MOF pores, followed by supramolecular surface modification with GST-affibody and collagenase. The affibody facilitated receptor-specific targeting toward HER2/EGFR, while collagenase aided in extracellular matrix degradation and improved tissue penetration. Therapeutic activation was triggered by external NIR light irradiation (808 nm), resulting in enhanced tumor accumulation and significant inhibition of tumor growth in vivo. Alibolandi et al. reported a Fe-porphyrin–linked Zr-MOF (FeP-Zr) engineered as an all-in-one CT/MR-visible, Dox-loaded, RGD-targeted nanoagent that combines imaging with synergistic chemo-PTT, achieving complete melanoma tumor suppression under 808 nm irradiation. Lastly, Zhang et al. synthesized a Zr–TCPP MOF decorated with TiO₂ (MOF@TiO₂) designed as a hypoxia-tolerant photosensitizer that under light, performs type II ¹O₂ PDT in normoxia and switches to oxygen-independent type I (O₂ ^•–/•OH) radical generation in severe hypoxia, enabling efficient ablation of hypoxic solid tumors (Figure ). Collectively, light-responsive Zr-MOFs exemplify how modular framework design, pore engineering, and surface functionalization can be combined to overcome fundamental limitations of PDT and PTT. By integrating photosensitizers, catalytic nanozymes, oxygen carriers, polymers, and targeting biomolecules within a single platform, Zr-MOFs enable programmable phototherapeutic activation, enhanced tumor selectivity, and robust performance in hypoxic tumor microenvironments.

8.

Cloaking antibody–MOF platform. The precoating of an antibody (IgG) to nMOF (MOF-808) particles can reduce the biomolecular corona. This preabsorption process can be assisted by optimization of the pore structure and defect sites of the MOF. Once the IgG is stabilized on the surface, the layer can provide a shield that is capable of inhibiting the protein corona. Based on preabsorption techniques, we fabricated a targetable antibody-modified nMOF. After each antibody is stabilized on the surface of the MOF, antibody–MOF complexes can target desired cancer cells. Reproduced with permission. Copyright 2024, ACS.

9.

(a) Schematic illustration of (a) the fabrication of MOF@TiO₂ nanoparticles and (b) their mechanism of photodynamic therapy (PDT) for treating hypoxic tumors. Reproduced with permission. Copyright 2021, ACS.

4.2.2. Temperature-Responsive

Temperature-responsive MOFs constitute a versatile class of smart materials in biomedical research, particularly for controlled cancer drug delivery. , Temperature gradients between diseased and healthy tissues, especially those induced by external heating or photothermal effects, can be utilized to enable site-specific drug release. Increasing the temperature weakens host–guest interactions within the porous framework, diminishing drug-MOF affinity and promoting accelerated cargo diffusion. Despite these advantages, maintaining structural integrity during thermal activation remains a key challenge, as the nanoscale thermal behavior, stability limits, and long-term robustness of MOFs under heating conditions are not yet fully understood.

In this context, Jimenez et al. reported highly porous Zr-MOFs (NU-1000 and NU-901) as efficient drug delivery platforms with exceptionally high loading capacities. A mild thermal treatment was applied to partially collapse the pore architecture, effectively suppressing burst release and enabling sustained drug delivery. The thermally modulated MOFs successfully delivered both a fluorescent probe (calcein) and the anticancer agent α-cyano-4-hydroxycinnamic acid (α-CHC). In vitro studies demonstrated enhanced intracellular delivery and increased cytotoxicity toward HeLa cancer cells compared with those of the free drug, highlighting the therapeutic benefit of thermally regulated release. These results demonstrate that controlled thermal treatment can be utilized to modulate drug release from Zr-MOFs, emphasizing their promise as temperature-responsive carriers for cancer therapy.

4.2.3. Ultrasound-Responsive

Ultrasound (US), a noninvasive mechanical energy modality with high tissue penetration capability, can be precisely focused on deep tumor regions while minimizing damage to surrounding healthy tissues. Upon ultrasonic irradiation, acoustic cavitation generates intense mechanical vibrations and shear forces at the cavitation interface, leading to transient increases in the local temperature and pressure. These extreme microenvironments promote sonochemical reactions that enhance ROS generation. In particular, the collapse of cavitation bubbles can induce hydrothermal pyrolysis of water, producing hydroxyl radicals (•OH), which may further recombine to form H₂O₂ in situ, thereby accelerating Fenton and Fenton-like reactions. Beyond its established diagnostic applications, ultrasound has, therefore, emerged as a versatile therapeutic trigger capable of enabling controlled drug release, inducing localized hyperthermia, and amplifying ROS production for effective tumor eradication.

Zirconium-based porphyrinic MOFs are particularly suitable for ultrasound-responsive applications due to their inherent sonosensitizing capability, robust structural stability, and capacity to incorporate catalytic metal centers. In a representative study, ultrasmall Mn-PCN-224 nanodots were developed as a renal-clearable sonosensitizer for enhanced sonodynamic therapy (SDT). By incorporating Mn²⁺ ions into PCN-224 and reducing the framework size to approximately 4 nm, the resulting nanodots exhibited catalase-like activity for decomposing endogenous H₂O₂ into O₂, while also minimizing ROS quenching due to shortened diffusion pathways (Figure ). Under low-intensity ultrasound irradiation, Mn-PCN-224 nanodots generated significantly higher levels of ROS compared to their larger counterparts, resulting in ∼91% tumor inhibition in A549 tumor-bearing mice. In addition, the porphyrin framework enabled photoacoustic imaging-guided therapy, while the ultrasmall size ensured rapid renal clearance and excellent biosafety, highlighting the potential of externally stimulated Zr-MOFs for deep-tissue cancer therapy. Complementing size- and composition-based strategies, cascade nanozyme designs have been explored to further amplify ultrasound-triggered therapeutic responses. Wang et al. engineered PCN-224­(Fe), integrated with platinum nanoparticles to construct a multifunctional ultrasound-activated nanozyme. Platinum nanoparticles imparted catalase-like activity, enabling in situ conversion of endogenous H₂O₂ into O₂ and alleviation of tumor hypoxia, while Fe-porphyrin nodes functioned as GPX4-mimicking centers to deplete intracellular glutathione. Upon ultrasound irradiation, the nanozyme generated abundant ROS, which induced ferroptosis and apoptosis in cancer cells. In vivo evaluation using a C6 glioma tumor model revealed substantial tumor growth inhibition (∼72%) along with significantly enhanced survival and minimal systemic toxicity, highlighting the therapeutic promise of ultrasound-responsive Zr-MOF nanozymes. Ultrasound-responsive Zr-MOFs have also been integrated into biohybrid systems to achieve programmable and immune-activating cancer therapy. Chen et al. employed PCN-224 as a sonosensitizer delivery module and electrostatically assembled onto genetically engineered E. coli to construct a programmable biohybrid system for cancer sonodynamic-immunotherapy. The bacteria enabled active tumor targeting, deep intratumoral penetration, and sustained catalase expression, thereby relieving tumor hypoxia and enhancing ultrasound-triggered ROS generation from PCN-224. Upon ultrasound irradiation, the biohybrid system achieved significant tumor growth inhibition, induced robust antitumor immune responses, and generated immune memory and abscopal effects, effectively suppressing tumor recurrence and metastasis. This work demonstrates how Zr-MOFs can function as stimulus-responsive therapeutic cargos within an advanced cancer drug-delivery and theranostic platform. Collectively, ultrasound-responsive Zr-MOFs demonstrate how deep-tissue-penetrating mechanical energy can be harnessed to activate SDT, enhance catalytic ROS generation, and synergize with immunotherapy.

10.

(a) Schematic illustration of the synthetic route to Mn-PCN-224 NDs (MM NDs). Created with BioRender.com. (b) Application of Mn-PCN-224 NDs in the treatment of hypoxic tumors. Reproduced with permission. Copyright 2025, ACS.

4.3. Multiple-Stimuli-Responsive

Multistimuli-responsive MOFs are engineered to take advantage of the complex and heterogeneous physicochemical features of diseased tissues, including variations in pH and temperature, as well as abnormal levels of biomolecules such as ATP, GSH, ROS, and phosphate ions. By integrating responsiveness to multiple endogenous and exogenous triggers within a single nanoplatform, these systems enable higher spatiotemporal precision, improved tumor selectivity, and enhanced therapeutic efficacy. Such multifunctional designs are particularly advantageous in the TME, where reliance on a single stimulus may be insufficient due to spatial and temporal heterogeneity. Table summarizes reported multistimuli-triggered Zr-MOFs for targeted cancer drug delivery.

4.3.1. Endogenous Multi-Stimuli-Responsive Zr-MOFs

Zhang et al. developed a multifunctional PCN-224-based Zr-MOF nanoplatform incorporating platinum nanoparticles, glucose oxidase (GOx), and an MnO₂ shell to construct a cascade-responsive therapeutic system. This platform simultaneously responded to acidic pH, elevated GSH, and H₂O₂ levels in tumors, enabling synergistic starvation therapy and chemodynamic therapy through amplified ROS generation. The integration of multiple catalytic components allowed continuous H₂O₂ production and efficient ROS amplification, resulting in strong anticancer efficacy in breast cancer cells and tumor-bearing mice with favorable biocompatibility. Similarly, Willner et al. reported a nucleic-acid-gated Zr-MOF capable of responding to multiple intracellular stimuli, including acidic pH, metal ions, and ATP. By integration of DNAzymes and ATP aptamers as molecular gatekeepers, the system enabled highly selective release of Dox in cancer cells through stimulus-dependent gate opening. This multistimuli-responsive approach resulted in increased cytotoxic effects against breast cancer cells while maintaining low toxicity toward normal tissues, underscoring the effectiveness of molecular logic gating in Zr-MOF-based drug delivery. Expanding endogenous cascade systems beyond conventional drug delivery, Yu et al. developed a PCN-223­(Fe) nanozyme platform that integrates glucose availability, H₂O₂, and mild acidity to drive synergistic nitric oxide (NO) and ROS generation. Iron-porphyrin linkers acted as NOS- and POD-like catalytic centers, while ultrasmall Au nanoparticles imparted GOx-like activity to enable continuous glucose oxidation and H₂O₂ generation. l-arginine loaded into the MOF pores served as an NO donor, which was catalytically converted into cytotoxic NO within the TME. Without relying on external stimuli, this endogenous multistimuli-responsive system achieved potent tumor inhibition in 4T1 breast cancer models through combined NO gas therapy, ROS-mediated damage, and starvation therapy with minimal systemic toxicity. Expanding the scope of ion-responsive multistimuli systems, Forgan et al. reported a phosphate-responsive Fe-doped MOF-808 nanocomposite for synergistic chemotherapy and chemodynamic therapy. Elevated intracellular phosphate levels induced framework degradation and carboplatin release, while Fe and Mn centers catalyzed Fenton-type reactions to generate hydroxyl radicals. Integration of Au nanoparticles further enabled imaging capability, demonstrating a theranostic platform effective in both 2D cell cultures and 3D tumor spheroids. Du et al. reported a universal silane-functionalization approach for the development of stimuli-responsive zirconium-based MOF drug delivery systems based on UiO-67­(Zr). Benzimidazole-terminated silanes are covalently anchored to surface Zr-oxo clusters via Zr–O–Si bonds, followed by capping with a cyclodextrin polymer (CDP) to form supramolecular nanovalves. These nanovalves effectively block premature drug leakage under physiological conditions while enabling acidic pH-triggered and α-amylase-triggered drug release, which are highly relevant to the tumor microenvironment. Dox-loaded UiO-67-SiBI@CDP nanoparticles exhibit excellent biocompatibility, efficient cellular uptake, and enhanced antitumor efficacy in HeLa cell lines and tumor-bearing mouse models with minimal systemic toxicity. This work clearly demonstrates how surface chemistry engineering of Zr-MOFs can enable endogenous stimuli-responsive cancer drug delivery, providing a versatile platform for controlled chemotherapy.

4.3.2. Hybrid Endogenous–Exogenous Multistimuli Systems

Combining endogenous and exogenous stimuli provides an additional level of therapeutic control. Mutalik et al. developed a transferrin-functionalized UiO-66 nanoplatform for targeted breast cancer therapy that integrates chemotherapy with photothermal and photodynamic modalities. Drug release and therapeutic activation were triggered by acidic tumor pH and near-infrared irradiation, while transferrin-mediated targeting enhanced selective uptake by cancer cells, leading to effective tumor ablation with minimal systemic toxicity. Ryu et al. reported a MOF-808 nanoparticle system for protein and photosensitizer codelivery to overcome tumor hypoxia and enhance PDT (Figure ). Catalase (CAT) was supramolecularly adsorbed onto the MOF surface (without chemical modification) to enable efficient intracellular delivery, while IR780 was loaded into the MOF pores as a photosensitizer. Upon cellular uptake, acidic intracellular conditions trigger CAT detachment, allowing CAT to convert endogenous H₂O₂ into O₂, thereby alleviating hypoxia and significantly enhancing ROS generation under 808 nm light irradiation. This work highlights a stimuli-responsive Zr-MOF platform for biomacromolecule delivery and improved PDT efficacy in cancer cells. Building on logic-gated hybrid strategies, Du et al. developed a physiologically stable, epitope-imprinted, double-gated PCN-224 system for tumor-targeted combination therapy. The porphyrinic Zr-MOF PCN-224 acts both as a drug carrier and a photosensitizer for PDT. The MOF surface is functionalized with diaminotriacetate-derived silanes (SiTA), enabling Fe³⁺ bridged DNA coordination, which serves as the first molecular gate and a secondary carrier for drug intercalation. An outer epitope-imprinted ZIF-8 shell provides active cancer-cell targeting, phosphate resistance, and a second gatekeeper layer. Drug release is governed by logic-gated stimuli, requiring acidic pH and DNase I, while 660 nm light irradiation activates PDT through singlet oxygen generation (Figure ). This multistimuli-responsive Zr-MOF platform enables precise, tumor-targeted delivery and synergistic photodynamic therapy–chemotherapy in both in vitro and in vivo settings. In addition, nucleic acid-responsive strategies have been explored to achieve higher enzymatic specificity. Su et al. reported an enzyme-responsive PCN-QADNA for cancer-selective PDT. In this system, the MOF surface was sealed with a DNA-based “lock” incorporating an apurinic/apyrimidinic (AP) site, which can be selectively cleaved by apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme that is overexpressed in many cancer cells. The DNA gate also incorporated a quencher that suppressed the porphyrin photoactivity under normal conditions. Upon APE1-mediated cleavage in cancer cells, the DNA lock was removed, restoring porphyrin photoactivity and enabling localized ROS generation under light irradiation. This system further amplified therapeutic efficacy through a positive-feedback mechanism, achieving pronounced tumor inhibition in vivo, while minimizing phototoxicity to healthy tissues.

11.

Schematic illustration of a MOF-supported catalase (CAT) delivery system designed to alleviate tumor hypoxia and enhance PDT in combination with a codelivered photosensitizer, IR780. Reproduced with permission. Copyright 2023, ACS.

12.

(a) Schematic illustration of the fabrication of a physiologically stable, epitope-imprinted, double-gated PCN-224 system. (b) Tumor-targeted combination therapy based on pH responsiveness, DNAzyme activity, and PDT. Reproduced with permission. Copyright 2025, ACS.

5. Zr-MOFs for Targeted Cancer Drug Delivery

Targeted drug delivery is a key goal in cancer nanomedicine, as it promotes enhanced drug accumulation at tumor sites while minimizing off-target toxicity to healthy tissues. Zr-MOFs have emerged as highly attractive platforms for targeted cancer therapy owing to their exceptional structural stability, high porosity, and readily tunable surface chemistry. In particular, the strong coordination affinity of Zr₆ clusters toward functional ligands enables the rational integration of both passive and active targeting strategies within a single nanoplatform, thereby improving tumor localization, cellular uptake, and intracellular drug delivery efficiency.

5.1. Passive Tumor Targeting via EPR Effect

Passive tumor targeting relies on the enhanced permeability and retention (EPR) effect, which originates from the leaky vasculature and deficient lymphatic drainage characteristic of solid tumors. The extravasation efficiency of nanoparticles is governed by the size of endothelial gaps and cross-endothelial transport channels. In general, nanoscale particles more readily penetrate tumor vasculature; however, excessively small nanoparticles are prone to rapid renal clearance, whereas overly large particles are susceptible to sequestration by the reticuloendothelial system (RES). Consequently, an optimal particle size window is essential to balance tumor accumulation and systemic circulation.

Most of the reported Zr-MOFs are typically engineered within the 50–200 nm size range, which is well suited for EPR-mediated tumor accumulation (Tables -). Within this regime, Zr-MOFs can preferentially extravasate into tumor tissues while minimizing the nonspecific distribution to healthy organs. UiO-66, UiO-67, MOF-808, PCN-224, and NU-series frameworks have demonstrated prolonged blood circulation and enhanced tumor retention when appropriately optimized for colloidal stability. Surface engineering strategies, including PEGylation, defect passivation, and polymer or protein coatings, are commonly employed to reduce opsonization and macrophage uptake, thereby extending circulation half-life and improving passive targeting efficiency (Tables –).

Despite these advantages, the EPR effect is highly heterogeneous and varies significantly across tumor types, stages, and patient populations. As a result, passive targeting alone is often insufficient to ensure efficient cellular internalization and intracellular drug delivery, underscoring the need to integrate active targeting mechanisms to further enhance therapeutic precision.

In addition to particle size optimization, emerging design strategies focusing on particle shape, surface charge, and mechanical flexibility have been shown to significantly influence passive tumor-targeting efficiency. Nonspherical nanostructures, such as rod-like or discoidal particles, can exhibit prolonged circulation and enhanced vascular margination compared to spherical counterparts, thereby improving tumor accumulation. , Moreover, surface charge modulation plays a crucial role in minimizing nonspecific protein adsorption and reticuloendothelial system clearance while facilitating improved tumor penetration.

Importantly, recent studies have highlighted the role of nanoparticle deformability and surface flexibility in enhancing transport across heterogeneous tumor vasculature and dense extracellular matrices, where rigid nanoparticles often face diffusion limitations. , In this context, soft polymer coatings, ,,,,,, lipid layers, and biomimetic surface engineering (e.g., protein-based cloaking) , can impart adaptive physicochemical properties that improve circulation stability and tumor-targeting efficiency.

These design strategies introduce additional parameters to address the variability of the EPR effect and enhance the passive targeting efficiency of the Zr-MOF nanocarriers in vivo. These approaches are especially applicable to Zr-MOF nanocarriers, as their tunable surface chemistry and coordination-based functionalization allow versatile modification with polymers, biomolecules, and targeting ligands, which are widely used to improve colloidal stability, extend circulation time, and enhance tumor accumulation (Tables –).

5.2. Active Targeting via Surface Functionalization with Ligands and Biomolecules

Active targeting approaches have been widely investigated to enhance the specificity and efficiency of nanocarrier-mediated drug delivery. Active targeting leverages pathophysiological differences between tumor and normal tissues, particularly the overexpression of specific receptors on cancer cells or tumor-associated endothelial cells, including folate, transferrin, epidermal growth factor receptors, and integrins. Functionalizing nanocarriers with ligands that selectively recognize these receptors enhances cellular targeting and facilitates receptor-mediated endocytosis, leading to increased intracellular drug accumulation.

Zr-MOFs offer a versatile platform for active targeting owing to the robust coordination chemistry of Zr₆ clusters, which enables stable and modular conjugation of diverse targeting ligands without compromising the framework integrity. Among small-molecule ligands, FA has been widely employed to functionalize UiO and MOF-808-type Zr-MOFs, resulting in enhanced uptake and cytotoxicity in folate receptor-overexpressing tumors. ,, Similarly, hyaluronic acid coatings facilitate CD44-mediated targeting while also serving as enzyme-responsive gatekeepers for controlled drug release. ,,,,

Beyond small molecules, peptide- and biomacromolecule-based targeting strategies further expand the targeting ability of Zr-MOFs. RGD peptides enable integrin-mediated targeting of tumor vasculature, while carbohydrate ligands such as galactose and chitosan derivatives promote selective uptake by hepatocellular carcinoma cells. ,,, More recently, antibody and affibody, ,, polymer, ,,,,,,,, and DNAzyme ,,,, functionalization has emerged as a powerful approach to achieve high targeting specificity. Antibody-modified Zr-MOFs MOF-808 and PCN-224 have demonstrated reduced protein corona formation, suppressed macrophage uptake, and receptor-specific delivery of chemotherapeutic agents or photosensitizers, underscoring the translational potential of biointerface-engineered Zr-MOF nanocarriers. ,

5.3. Targeted Intracellular Delivery and Stimuli-Responsive Release

Zr-MOFs can be effectively internalized by cancer cells via multiple endocytic pathways, including clathrin-mediated endocytosis, caveolae-mediated uptake, and macropinocytosis, depending on factors such as particle size, surface charge, and ligand composition. , Surface protonation, amine functionalization, or peptide modification can further promote endosomal escape via the proton sponge effect, thereby facilitating cytosolic drug release and enhancing therapeutic efficacy. ,−

Controlled framework degradation is a critical determinant of biosafety and treatment reliability. Zr-MOFs must degrade in a predictable manner into biocompatible components, avoiding abrupt metal-ion release or excessive linker accumulation. Rational design strategies, such as tuning metal–ligand coordination strength or incorporating stimuli-responsive motifs, enable programmable degradation and sustained drug release while minimizing acute toxicity. A key advantage of Zr-MOF nanocarriers is their ability to integrate targeted delivery with stimulus-responsive activation. Targeting ligands improve tumor and cellular specificity, while endogenous stimuli (e.g., pH, enzymes, ATP, GSH, phosphate ions), exogenous triggers (e.g., light, heat, ultrasound), or their combinations enable on-demand drug release or therapeutic activation at the tumor site. A general schematic illustration of stimuli-responsive Zr-based targeted cancer drug delivery is presented in Figure . This synergistic integration minimizes premature payload leakage during circulation and maximizes intracellular drug activation, collectively improving therapeutic indices and treatment precision.

13.

An overview of stimuli-responsive Zr-MOF platforms for targeted cancer nanomedicine. Created with BioRender.com.

6. Conclusion and Prospective Directions

Over the past decade, an extensive body of research has rapidly emerged, exploring Zr-MOFs for drug delivery. This progress has been enabled by advances in controlling particle size and morphology, the high adaptability of Zr-MOFs to postsynthetic modification, their large cargo-loading capacity, excellent stability in aqueous media, good colloidal dispersibility, and overall biocompatibility. Within this context, stimuli-responsive Zr-MOFs have emerged as a highly versatile and effective class of nanocarriers for targeted cancer therapy. Their robust framework stability, high porosity, and adaptable surface chemistry enable efficient drug encapsulation, precise functionalization, and programmable degradation. By harnessing endogenous TME cues such as pH, redox, ATP, enzyme activity, and ion gradients together with externally applied physical stimuli, including light, heat, and ultrasound, Zr-MOF-based platforms provide exceptional opportunities for spatiotemporally controlled therapeutic activation. Moreover, the emergence of multistimuli-responsive and logic-gated Zr-MOF systems highlights how rational framework and biointerface engineering can effectively address tumor heterogeneity and enhance therapeutic precision. Looking forward, the following prospective research directions are expected to define the next generation of Zr-MOF-based targeted cancer nanomedicines:

• (i)Exploring the coordination of Zr⁴⁺ ions with diverse classes of organic ligands to create new families of Zr-MOFs represents an important direction for expanding structural and functional diversity. In parallel, the development of eco-friendly and sustainable synthetic strategies is essential to improve scalability, commercial viability, and broad practical application. Despite significant progress in synthetic methodologies, substantial opportunities remain for further optimization in terms of efficiency, reproducibility, and therapeutic impact.
• (ii)Future Zr-MOF designs should prioritize clinically reliable and tumor-specific stimuli, with particular emphasis on triggers that display consistent spatial and temporal gradients across different tumor types. Hierarchical or logic-gated systems that respond only to the simultaneous presence of multiple stimuli offer a promising strategy to minimize off-target activation and enhance therapeutic selectivity.
• (iii)Accurate control over framework degradation and in vivo clearance is critical for the safe and effective use of Zr-MOFs. Engineering Zr-MOFs with programmable disassembly kinetics and well-defined degradation pathways can enhance biosafety while preserving therapeutic efficacy, particularly under phosphate-rich physiological conditions.
• (iv)Biointerface engineering will be critical for improving the in vivo performance and translational potential of Zr-MOF-based nanomedicines. Strategies that control protein corona formation, minimize immunogenicity, and allow modular conjugation of targeting ligandssuch as antibodies, affibodies, or peptidescan significantly enhance circulation stability and tumor specificity. Moreover, simplified supramolecular and noncovalent functionalization strategies are expected to offer superior scalability and reproducibility compared with complex multistep chemical modifications.
• (v)The integration of Zr-MOFs with emerging therapeutic modalities, including immunotherapy, ferroptosis, gas therapy, and imaging-guided treatment, offers a promising strategy for synergistic cancer therapy. Such multifunctional platforms can enable concurrent tumor ablation, immune activation, and real-time therapeutic monitoring, thereby enhancing overall treatment efficacy.
• (vi)Future light-responsive Zr-MOFs should emphasize deeper-tissue activation strategiessuch as NIR-II, X-ray, or ultrasound triggeringtogether with oxygen-independent or hypoxia-tolerant photochemical pathways and immune-modulating nanoreactors capable of inducing immunogenic cell death. Progress toward chemically simplified, defect-controlled, and GMP-compatible architectures, incorporating minimal yet functional surface coatings, standardized imaging readouts, and well-defined pharmacokinetic and toxicological profiles, will be critical for enabling image-guided and patient-tailored clinical translation.

Finally, accelerating clinical translation will require standardized evaluation frameworks and the use of clinically relevant models. Unified toxicity and pharmacokinetic benchmarks, together with advanced tumor models, such as patient-derived xenografts and 3D organoids, are essential for bridging the gap between preclinical performance and clinical applicability. Through continued interdisciplinary collaboration and translationally oriented design, stimuli-responsive Zr-MOF nanomedicines are well positioned to advance precision cancer therapy.

#.

R.G., M.S.H., and S.G. contributed equally.

The authors declare no competing financial interest.