Enzymes orchestrate chemical transformations with unparalleled efficiency and specificity, a prowess derived from evolutionarily optimized active sites and finely tuned microenvironments [1], [2], [3], [4], [5], [6]. Their catalytic perfection, however, is often circumscribed by inherent vulnerabilities—structural fragility, narrow operational windows (pH, temperature), and high production costs [7]. Consequently, considerable efforts have been directed toward developing biomimetic alternatives that emulate enzymatic function while enhancing robustness, substrate adaptability, and operational flexibility [8], [9], [10].
Molecularly imprinted polymers (MIPs), initially designed to mimic antibody-antigen recognition [11], [12], [13], [14], [15], [16], [17], [18], have emerged as a versatile platform for this purpose. When this recognition‑centered paradigm is extended to incorporate catalytic functionality within nanoconfined spaces, MIPs evolve into molecularly imprinted nanoreactors (MIRs) [19]. As a distinct catalytic paradigm, MIRs intersects with, yet meaningfully extends beyond, established categories of enzyme-mimetic systems. While nanozymes focus primarily on replicating the catalytic active sites of enzymes—often through inorganic nanomaterials [20]—MIRs integrate molecular imprinting to create tailored binding cavities that confer substrate selectivity, thereby addressing a key limitation of conventional nanozymes [21]. Unlike molecular catalysts, which operate in homogeneous media, MIRs offer heterogeneous, reusable platforms with programmable microenvironments that stabilize transition states and regulate reaction pathways [22], [23]. Furthermore, MIRs differ from generic hybrid catalytic systems by emphasizing the synergistic co-design of tailored recognition sites, catalytic centers, and nanoconfined reaction spaces within a unified architecture [23]. Thus, MIRs are best viewed as integrated nanoreactors that combine the selectivity of molecular imprinting, the tunability of synthetic catalysis, and the robustness of engineered nanomaterials.
The fundamental goal in MIR design is to faithfully emulate the core principles of enzymatic catalysis. This involves: (1) mimicking the active site by precisely positioning catalytic moieties (e.g., acids, bases, nanozymes, metal complexes) within the imprinted cavity, often using transition-state analogues (TSAs) [24], [25], [26], product analogues (PAs) [27], [28], [29], or substrate analogues (SAs) [30], [31] as templates (Scheme 1, Scheme 2); (2) replicating the catalytic process where the pre-organized functional groups cooperate to facilitate bond cleavage/formation, with performance quantifiable via Michaelis-Menten kinetics (e.g., KM, kcat, kcat/KM) to allow direct comparison with natural enzymes [32], [47]; and (3) engineering the catalytic microenvironment, where the polymer matrix surrounding the active site modulates local polarity, hydrophobicity, and electrostatics to pre-concentrate substrates, stabilize transition states, and control product diffusion [33], [34], [35]. Despite these advances, the field was constrained by persistent challenges—template leakage, binding-site heterogeneity, and mass-transfer limitations—that collectively undermine catalytic efficiency and reproducibility [32]. While architectural innovations (e.g., hierarchically porous/core-shell structure [36], [37], [38], [39], [40]) and advanced fabrication techniques (like cryo-/micellar imprinting [41], [42], [43], [44], [45], [46]) have alleviated some issues (Scheme 2), a unified framework to guide the rational design of high-performance MIRs is still lacking. Critical questions remain unanswered: How can we standardize activity metrics across diverse MIR platforms? What are the governing principles for achieving high turnover? Most importantly, how can we achieve synergistic co-design of active sites and microenvironments to bridge the gap between MIRs and enzymatic efficiency?
This review aims to bridge these gaps by establishing a comprehensive, structure-activity-oriented framework for MIRs. We first deconstruct the evolution from simple imprinted polymers to sophisticated nanoreactors, critically analyzing cutting-edge strategies for active-site engineering (coordination anchoring, post-imprinting modification, spatial encapsulation) and microenvironment programming (cofactor regulation, tandem catalysis, nanoconfinement, electronic effects). We then evaluate their transformative applications in environmental remediation, biosensing, pharmaceutical synthesis, and energy conversion, with a critical emphasis on performance relative to natural enzymes and real-world operational challenges. Finally, we delineate future research trajectories, highlighting the integration of single-atom catalysts, in situ spectral analysis, and synthetic biology interfaces as pathways to advance MIRs from laboratory toward industrial biocatalysis and programmable medicine.