Self-assembled nanostructures of amphiphilic and double hydrophilic block copolymers have been increasingly utilized as potent polymeric nanocarriers of therapeutic drugs, genes, bioactive molecules, and imaging/contrast agents due to improved water solubility, bioavailability, and extended blood circulation duration. Though passive and active targeted drug delivery strategies have long been proposed to promote desirable drug accumulation specifically at the disease sites, the introduction of stimuli-responsiveness into self-assembled block copolymer nanocarriers can additionally lead to controlled/triggered release of therapeutic/imaging agents into target pathological tissues and cells, with concomitant advantages of enhanced delivery efficiency and therapeutic efficacy. Appropriately designed stimuli-responsive block copolymer assemblies can exhibit chemical structure transformation, microstructural rearrangement and inversion, or even disassembly into unimers or smaller ones under external stimuli such as pH, temperature, ion strength, redox potential, light, electric, and magnetic fields, and specific bioactive molecules and metabolites. Compared to normal tissues, pathological sites such as tumor tissues typically exhibit vascular abnormalities, weak acidity (∼pH 6.8), abnormal temperatures, over-expressed proteins and enzymes, hypoxia, high levels of metabolites and reactive small molecule species, etc. Moreover, upon cellular uptake, drug-loaded polymeric nanocarriers will be subjected to intracellular pH gradients (pH 5.9–6.2 in early endosomes and pH 5.0–5.5 in late endosomes and lysosomes) and redox and H₂O₂ gradients within different cell organelles and the cytosol. Thus, block copolymer nanocarriers responsive to the above described bio-relevant stimuli or biochemical signals characteristic of pathologic tissues and cells will provide an alternative type of “active targeting” strategy, which can be utilized to further boost therapeutic efficacy and imaging sensitivity via disease site-specific delivery and controlled release. A variety of extracellular or intracellular stimuli innate to disease sites, such as mildly acidic pH, temperature, enzymes (matrix metalloproteinase, β-glucuronidase, and phosphatase), oxidative/reductive microenvironments, and abnormal levels of bioactive molecules or metabolites, have been utilized for this purpose. In this review, we summarize recent advances in stimuli-responsive block copolymer assemblies which are responsive to tumor and intracellular microenvironments and their applications in anticancer drug delivery and enhanced imaging sensitivity.

Being responsive and adaptive to external stimuli is an intrinsic feature characteristic of all living organisms and soft matter. Specifically, responsive polymers can exhibit reversible or irreversible changes in chemical structures and/or physical properties in response to a specific signal input such as pH, temperature, ionic strength, light irradiation, mechanical force, electric and magnetic fields, and analyte of interest (e.g., ions, bioactive molecules, etc.) or an integration of them. The past decade has evidenced tremendous growth in the fundamental research of responsive polymers, and accordingly, diverse applications in fields ranging from drug or gene nanocarriers, imaging, diagnostics, smart actuators, adaptive coatings, to self-healing materials have been explored and suggested. Among a variety of external stimuli that have been utilized for the design of novel responsive polymers, enzymes have recently emerged to be a promising triggering motif. Enzyme-catalyzed reactions are highly selective and efficient toward specific substrates under mild conditions. They are involved in all biological and metabolic processes, serving as the prime protagonists in the chemistry of living organisms at a molecular level. The integration of enzyme-catalyzed reactions with responsive polymers can further broaden the design flexibility and scope of applications by endowing the latter with enhanced triggering specificity and selectivity. In this tutorial review, we describe recent developments concerning enzyme-responsive polymeric assemblies, nanoparticles, and hydrogels by highlighting this research area with selected literature reports. Three different types of systems, namely, enzyme-triggered self-assembly and aggregation of synthetic polymers, enzyme-driven disintegration and structural reorganization of polymeric assemblies and nanoparticles, and enzyme-triggered sol-to-gel and gel-to-sol transitions, are described. Their promising applications in drug controlled release, biocatalysis, imaging, sensing, and diagnostics are also discussed.

Solution self-assembly of block copolymers (BCPs) typically generates spheres, rods, and vesicles. The reproducible bottom-up fabrication of stable planar nanostructures remains elusive due to their tendency to bend into closed bilayers. This morphological vacancy renders the study of shape effects on BCP nanocarrier-cell interactions incomplete. Furthermore, the fabrication of single BCP assemblies with built-in drug delivery functions and geometry-optimized performance remains a major challenge. We demonstrate that PEG-b-PCPTM polyprodrug amphiphiles, where PEG is poly(ethylene glycol) and PCPTM is polymerized block of reduction-cleavable camptothecin (CPT) prodrug monomer, with >50 wt % CPT loading content can self-assemble into four types of uniform nanostructures including spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Staggered lamellae outperform the other three nanostructure types, exhibiting extended blood circulation duration, the fastest cellular uptake, and unique internalization pathways. We also explore shape-modulated CPT release kinetics, nanostructure degradation, and in vitro cytotoxicities. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological performance opens up new horizons for exploring next-generation BCP-based drug delivery systems with improved efficacy.