Zhixuan Zhou

Pharmacological treatments, common methods for inhibiting tumor cell proliferation, often concurrently induce secondary immunosuppression. Reprogramming tumor-associated macrophages (TAMs) from an M2 to M1 phenotype via photosensitization offers a promising strategy to relieve the immunosuppressive tumor microenvironment, which may serve as an effective approach to reverse secondary immunosuppression. However, the efficacy of current photosensitizers is limited due to the insufficient macrophage specificity and suboptimal photosensitivity. To address these challenges, we here reported a proximity-driven strategy that optimizes the spatial positioning of photosensitizer precursors (PPs) relative to the active center of overexpressed enzymes, substantially enhancing the activation efficiency and selectivity of PPs in M2 macrophages. Simultaneously, through the integrated screening of photosensitizer performance, we developed a novel PP (NP-YB-5) that demonstrates superior efficacy (72.1%) in inducing macrophage polarization compared to both current immune adjuvants and earlier-generation responsive precursors (<60%). More importantly, phototherapy mediated by NP-YB-5 not only eliminates primary tumors exhibiting secondary immunosuppression but also inhibits the progression of distal (metastatic) tumors, achieving a statistical cure rate of 85%. Our work presents a novel design paradigm for the development of potent molecular tools in macrophage-mediated photosensitization, offering a promising approach for overcoming drug-induced secondary immunosuppression of tumors.

Accurate differentiation of benign and malignant breast tumors is paramount for establishing schemes of breast cancer treatment and prognosis. Here we report a near-infrared (NIR) fluorescence probe (YF-1) with the overexpressed cathepsin C (CTSC) in metastatic breast tumors as the detecting substrate. This probe allows accurate identification of malignant tumor tissue specimens among tumor tissue specimens with unknown properties in a blind study. Importantly, a series of visible to NIR CTSC-activated fluorescence probes based on the same strategy realize effective identification of malignant tumor tissues, suggesting that CTSC could be the specific identification substrate of malignant breast tumors. Furthermore, a hydrophilic PEG moiety is coupled into YF-1, producing another CTSC-activated NIR probe (YF-2). YF-2 has excellent tumor-targeting capability, enabling the visualization of lung-metastatic breast tumors. The excellent detection accuracy and construction versatility of CTSC probes pave the way for preoperative diagnosis of malignant breast tumors.

Optical imaging is a powerful tool for early disease detection and effective treatment planning, but its accuracy is often compromised by the uptake of imaging materials by the mononuclear phagocyte system (MPS). Herein, we leverage multivalent host-guest interactions between cyanine dyes and β-cyclodextrin polymers to develop supramolecular probes with enhanced stability, optical, and transport profiles for accurate in vivo imaging. These multivalent interactions not only ensure the stability of the probes but also enhance fluorescence efficiency by minimizing nonradiative decay. Our self-assembly approach effectively modulates probe size and surface properties, enabling evasion of MPS clearance and promoting prolonged bloodstream circulation, thereby improving the signal-to-background ratio for imaging. The effectiveness of our design is demonstrated by substantial advancements in the early diagnosis of acute kidney injury and by providing high-contrast imaging and precise surgical navigation across various tumor models. Our strategy not only advances optical imaging materials toward clinical translation but also establishes a versatile platform applicable to multiple imaging modalities.

The complex dynamics and transience of assembly pathways in living systems complicate the understanding of these molecular to nanoscale processes. Current technologies are unable to track the molecular events leading to the onset of assembly, where real-time information is imperative to correlate their rich biology. Using a chemically designed pro-assembling molecule, we map its transformation into nanofibers and their fusion with endosomes to form hollow fiber clusters. Tracked by phasor-fluorescence lifetime imaging (phasor-FLIM) in epithelial cells (L929, A549, MDA-MB 231) and correlative light-electron microscopy and tomography (CLEM), spatiotemporal splicing of the assembly events shows time-correlated metabolic dysfunction. The biological impact begins with assembly-induced endosomal disruption that reduces glucose transport into the cells, which, in turn, stymies mitochondrial respiration.

The polymerization of biomolecules is a central operation in biology that connects molecular signals with proliferative and information-rich events in cells. As molecules arrange precisely across 3-D space, they create new functional capabilities such as catalysis and transport highways and exhibit new phase separation phenomena that fuel nonequilibrium dynamics in cells. Hence, the observed polymer chemistry manifests itself as a molecular basis leading to cellular phenotypes, expressed as a multitude of hierarchical structures found in cell biology. Although many milestone discoveries had accompanied the rise of the synthetic polymer era, fundamental studies were realized within a closed, pristine environment and that their behavior in a complex multicomponent system remains challenging and thus unexplored. From this perspective, there is a rich trove of undiscovered knowledge that awaits the polymer science community that can revolutionize understanding in the interactive nanoscale world of the living cell.In this Account, we discuss the strategies that have enabled synthetic polymer chemistry to be conducted within the cells (membrane inclusive) and to establish monomer design principles that offer spatiotemporal control of the polymerization. As reaction considerations such as monomer concentration, polymer growth dynamics, and reactivities are intertwined with the subcellular environment and transport processes, we first provide a chemical narrative of each major cellular compartment. The conditions within each compartment will therefore set the boundaries on the type of polymer chemistry that can be conducted. Both covalent and supramolecular polymerization concepts are explored separately in the context of scaffold design, polymerization mechanism, and activation. To facilitate transport into a localized subcellular space, we show that monomers can be reversibly modified by targeting groups or stimulus-responsive motifs that react within the specific compartment. Upon polymerization, we discuss the characterization of the resultant polymeric structures and how these phase-separated structures would impact biological processes such as cell cycle, metabolism, and apoptosis. As we begin to integrate cellular biochemistry with in situ polymer science, we identify landmark challenges and technological hurdles that, when overcome, would lead to invaluable discoveries in macromolecular therapeutics and biology.

Nanostructure-based functions are omnipresent in nature and essential for the diversity of life. Unlike small molecules, which are often inhibitors of enzymes or biomimetics with established methods of elucidation, we show that functions of nanoscale structures in cells are complex and can implicate system-level effects such as the regulation of energy and redox homeostasis. Herein, we design a platinum(II)-containing tripeptide that assembles into intracellular fibrillar nanostructures upon molecular rearrangement in the presence of endogenous H₂O₂. The formed nanostructures blocked metabolic functions, including aerobic glycolysis and oxidative phosphorylation, thereby shutting down ATP production. As a consequence, ATP-dependent actin formation and glucose metabolite-dependent histone deacetylase activity are downregulated. We demonstrate that assembly-driven nanomaterials offer a rich avenue to achieve broad-spectrum bioactivities that could provide new opportunities in drug discovery.

Catenated cages represent chemistry’s challenging synthetic targets because a three-dimensional assembly is necessary for their formation. Herein, a cyclic bis[2]catenane is constructed through the coordination-driven self-assembly of the interlocked bis-metallacage, by the 90° Pt(II) heteroligation of the endo-functionalized double-bridged tweezer bearing pyridyl moieties and the tetra-carboxylated linker. NMR spectrometry, X-ray crystallography and mass spectrometry confirm the formation of a cyclic bis[2]catenane with “∞”-shaped topology via a 14-component self-assembly. Particularly, reversibly responsive transformation between the bis[2]catenane and the bis-metallacage can be realized by guest exchange, concentration effect and solvent effect. This work represents a novel example of a cyclic cage-based [2]catenane oligomer.

In this report, we describe the synthesis of two porphyrin-containing Pt(II) supramolecular assemblies via coordination-driven self-assembly. X-ray crystallographic analysis on one assembly reveals that the metalla-assembly formation imposes large interchromophore distances, leading to a higher ¹O₂ generation efficiency, relative to the corresponding small molecular precursors. The metalla-assemblies were examined as photosensitizers for photodynamic therapy as the potential reduction of the unfavorable self-aggregation phenomenon. In vivo and in vitro investigations demonstrate that the metalla-assemblies exhibit enhanced anticancer activity with minimal dose requirement and side effects comparable to the small molecule precursors. Thus, our work demonstrates that self-assembly provides a promising methodology for enhancing the therapeutic effectiveness of anticancer agents.