Hierarchical design of hybrid carriers to control nutrient fate

Introduction

Efficient nutrient delivery systems are increasingly critical in functional foods and nutraceuticals, where bioactive compounds must remain stable during processing and storage while retaining their ability to be effectively absorbed in the body. The quest for precision nutrition hits a wall: delivery systems must be robust enough to survive food processing, yet sufficiently adaptive to release their cargo in the body (Wang et al., 2024). To address this challenge, a variety of delivery strategies have been developed, including encapsulation technologies, emulsion-based carriers, nanoparticles, and protein–polysaccharide complexes designed to improve the protection and transport of sensitive nutrients. Conventional encapsulation, which relies on static physical barriers for protection, pays for its stability with a loss of bioavailability. This inherent conflict exists because these strategies lack the hierarchical architecture necessary to separate stability from digestibility (Zhang and Jia, 2023). As a result, we cannot yet program the fate of bioactive nutrients with precision.

To move beyond, we look to nature for inspiration. Biological hybrids like casein micelles and ferritin master the balance, sequestering inorganic cargo within adaptive matrices (Acevedo-Fani et al., 2020). Nature achieves this not through simple encapsulation, but through a hierarchical orchestration of hard and soft interfaces that prevents cargo degradation while ensuring release upon physiological triggers. Mirroring this natural blueprint defines a clear design principle: moving from stochastic mixtures to precisely engineered organic–inorganic architectures (Wei et al., 2023). By treating the nutrient not merely as a passive additive but as a “guest” confined within a programmable ‘host’ matrix, we can impose structural order onto the chaotic environment of the gastrointestinal tract.

This review introduces a hierarchical design framework. We propose that exploiting hierarchical degrees of freedom decouples protection from release via three mechanisms: thermodynamic locking (nanoscale), structural gating (mesoscale), and mechanical integrity (macroscale). By integrating these levels of structural control, this framework transitions nutrient delivery from empirical formulation to deterministic science, enabling carriers that are as intelligent as they are edible.

Hierarchical design principles

The development of functional materials is governed by a fundamental trade-off, known as the “Banana Curve”, where an inverse relationship exists between two critical parameters (Cranford, 2025). In nutritional delivery, this inherent conflict exists between stability and bioavailability (Figure 1A). While high solubility and rapid dissolution are prerequisites for bioavailability, they simultaneously expose bioactive agents to environmental degradation, premature release, and chemical incompatibility (Jalali-Jivan et al., 2022). Strategies to enhance stability, such as crystallization or dense encapsulation, often impose structural rigidity that impedes timely release at the target site, rendering the cargo effectively inert (Zhang et al., 2023a).

This dichotomy imposes a strict boundary condition: optimal solutions are shackled to a Pareto frontier, beyond which conventional materials science struggles to tread (Cranford, 2025). Conventional strategies, such as physical mixing or emulsification, inevitably fail to transcend this curve. They lack the architectural complexity to survive the hostile environment of the gastrointestinal (GI) tract. The GI tract is not merely a conduit but a relentless biochemical filter, sequentially attacking cargo with gastric acid, intestinal proteases, and mucus entrapment. Under this, unprotected nutrients are dismantled long before absorption (Zhang et al., 2024). For instance, simple mixing of iron and iodine in fortification strategies leads to redox reactions that destabilize both nutrients, while naked insulin suffers immediate proteolysis, yielding a bioavailability of <0.1% (Liu et al., 2025; Yang et al., 2025).

Escaping the “Banana Curve” necessitates decoupling protection from release. We must therefore move beyond bulk material properties and instead exploit “hierarchical degrees of freedom.” By independently tuning architecture at the nano-, meso-, and macro-scales, we can effectively “program” the nutrients’ journey: maintaining rigorous defense against environmental stress, yet ensuring rapid bioavailability upon specific physiological triggers (Figure 1B). A systematic overview of representative organic/inorganic hybrid delivery systems employing these rational design strategies is summarized in Table 1.

TABLE 1. Design strategies and functional outcomes of hybrid delivery systems.

At the nano-scale, the primary degree of freedom lies in the thermodynamic orchestration of binding motifs. In peptide-metal chelates, specific amino acid side chains are exploited to sequester ions, simultaneously suppressing off-target reactivity while ensuring solubility. For instance, stabilizing Cerium (III) within fish skin collagen harnesses the cooperative coordination of carboxyl groups (Asp, Glu) and tryptophan indole rings; this assembly forms a robust macrocycle that mitigates cytotoxicity and averts precipitation in the alkaline intestinal milieu (Wu et al., 2025). Beyond sequestration, nano-engineering permits the precise dictation of oxidation states. In oat protein nanofibrils, the in situ incorporation of sodium ascorbate locks iron into its bioavailable ferrous (Fe²⁺) form, boosting human absorption by 1.76-fold compared to ferrous sulfate (Zhou et al., 2025). This reductive stabilization evolves further in “NuMOFs” for double-fortified salt, where Vitamin C serves as a synthesis modulator. By strictly maintaining the Fe (II) state, the MOF architecture resolves the intractable conflict between iron and iodine—preventing iron-catalyzed iodine sublimation—and stabilizes both micronutrients within a single lattice without energy-intensive anoxic processing. Ultimately, thermodynamic stability can be coupled with kinetic programmability (Yang et al., 2025). In Zirconium-based MOFs, capping coordination sites with folate creates a “kinetic gate”: strictly blocking degradation in neutral environments, yet triggering rapid framework collapse upon exposure to bloodstream phosphates, thereby synchronizing release with absorption (Zou et al., 2025).

At the meso-scale, manipulating porosity, tortuosity, and interfacial chemistry grants a second degree of freedom: modulating diffusion and interaction kinetics independent of the cargo’s intrinsic chemistry. Biomimetic strategies, such as “pinecone-inspired” microcages, exploit structural anisotropy to construct stimuli-responsive barriers. By anchoring cellulose nanofibril shells with polypeptides, these carriers function as pH-actuated gates: maintaining porosity under acidic conditions for loading, yet mechanically collapsing in the intestinal environment to sequester macromolecular payloads (Zhang et al., 2020). In the dry state, Atomic Layer Deposition (ALD) similarly redefines particle mechanics. Conformal inorganic nanofilms (e.g., silica, titania) modify surface energy and inter-particle cohesion at the nanoscale, inducing a macroscopic transformation in flowability (Zhang et al., 2023a). Here, precise interfacial engineering overrides the intrinsic cohesivity of bulk materials, dictating the aerodynamic de-agglomeration crucial for inhalation therapies. Finally, supramolecular metal-polyphenol networks (MPNs) offer dual-function shielding for hydrophobic cargoes: providing a robust physical barrier against UV and thermal degradation while imparting the surface charge necessary for aqueous dispersibility (Chai et al., 2025).

The final degree of freedom lies in macro-scale mechanics, which govern the system’s physical endurance against digestive shear and its hydrodynamic interaction with the mucosal lining. Fortifying polysaccharide microgels with phenolic-metal coordination frameworks elevates their Young’s modulus, effectively armoring probiotic cargo against gastric disintegration to facilitate viable colonic delivery (Zhang et al., 2024). Beyond assembly, physical processing acts as a macroscopic determinant. In the stone ball milling of whole fish powder, precise energy regulation preserves protein integrity while pulverizing particles below 30 microns—a critical threshold that eliminates grittiness and maximizes the surface area for enzymatic hydrolysis (Irshad et al., 2024). Rehydration kinetics are equally programmable: pre-treatment of casein-rich feeds with trisodium citrate modulates micellar calcium equilibrium prior to spray drying, strictly tailoring bulk density and wettability for rapid dissolution (Zhong et al., 2025).

The convergence of these hierarchical tiers—nano-scale thermodynamic orchestration, meso-scale gating, and macro-scale mechanical reinforcement—fundamentally rewrites the design rules. We are no longer hostage to the binary trade-off where stability mandates indigestibility. Instead, we can engineer systems that are robust in storage yet structurally responsive at the site of action.

Emerging approach and future perspectives

Nutrient delivery is pivoting from traditional empirical formulation to rational, ab initio design. While historical discovery relied on serendipity or iterative modification, the combinatorial expanse of metal-organic frameworks (MOFs)—comprising millions of theoretical structures—renders such Edisonian experimentation statistically futile (Menon and Fairen-Jimenez, 2025). High-throughput computational screening and machine learning (ML) now navigate this complexity, guiding researchers toward materials with strictly targeted yet previously counter-intuitive properties (Cranford, 2025). Crucially, toxicological validation has moved upstream. Computational pipelines now screen thousands of architectures for biocompatibility long before wet-lab synthesis begins. Trained on vast toxicological datasets of linkers and nodes, ML algorithms predict safety profiles with >80% accuracy. This in silico screening systematically eliminates toxic structures, isolating robust, biocompatible scaffolds—such as Zirconium-based frameworks—from the noise. This shift may reduce the historical reliance on a handful of legacy carriers (e.g., ZIF-8, MIL-101), catalyzing the emergence of a diverse library of bespoke vehicles, each computationally tailored for specific physiological interactions (Menon and Fairen-Jimenez, 2025).

The horizon of nutrient delivery is defined by autonomous systems that transcend passive transport to mediate specific molecular interactions with the host. Emerging vectors co-opt pathological markers as entry portals. In diabetic pathology, the upregulation of the proton-coupled folate transporter (PCFT) offers a precise molecular target; folate-decorated PCN-777 MOFs leverage this to selectively target endogenous uptake pathways, concentrating insulin in diseased tissue while sparing healthy cells (Zou et al., 2025). Parallel precision is achieved in hepatic targeting, where galactose-rich microgels exploit hepatocyte asialoglycoprotein receptors for site-specific accumulation (Zhang et al., 2024). Ultimately, these architectures function not as mere vessels but as stimuli-responsive systems, integrating environmental inputs (e.g., serum phosphate, pH gradients) to actuate release, thereby elevating nutrients from dietary supplements to precision therapeutics.

The rigid dichotomy between inert carrier and active cargo is becoming increasingly blurred, giving rise to systems characterized by intrinsic bioactivity, where the vehicle itself acts as a therapeutic agent. In Mesona chinensis polysaccharide microgels, the structural polyphenols serve a dual mandate: functioning as the physical scaffold while simultaneously modulating gut microbiota—specifically promoting Akkermansia proliferation—as potent prebiotics (Zhang et al., 2024). Consequently, carrier degradation releases a secondary therapeutic stream, establishing a synergistic gut-liver protection axis alongside the primary probiotic payload. Oat protein nanofibrils display similar bio-functionality; their glutamine-rich domains do not merely stabilize iron nanoparticles but actively potentiate absorption, transforming the stabilizer into a functional enhancer (Zhou et al., 2025). Finally, this synergy extends to supramolecular sensory engineering. In carvacrol-loaded cyclodextrin-MOFs, host-guest electronic interactions simultaneously solubilize the volatile payload, mask its organoleptic pungency, and amplify its antioxidant capacity (Ates and Yildiz, 2025).

The design paradigm for functional materials is increasingly shifting from static encapsulation to the engineering of dynamic biomaterial interfaces. By exploiting hierarchical degrees of freedom—spanning from nanoscale electronic states to macroscopic rheology—researchers can now develop systems with programmed degradation profiles and enhanced therapeutic efficacy. This approach addresses persistent delivery challenges, facilitating advancements such as highly bioavailable oral insulin, organoleptically stable iron fortification, and targeted probiotic release. Ultimately, integrating structural complexity with computational design allows the field to transcend the historical limitations of the “Banana Curve,” establishing a robust framework for multidimensional material innovation.

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Footnotes

Edited by: Kamal Essifi, Chouaib Doukkali University, Morocco

Reviewed by: Sahil Malhotra, American College Dublin, Ireland