Jui-I Chao

Targeted protein degradation has emerged as a transformative therapeutic modality in cancer therapy, enabling the elimination of undruggable proteins and overcoming conventional small‐molecule resistance. Therapeutic approaches such as endocytosis‐targeting chimera (ENDOTAC) and autophagy‐targeting chimera (AUTOTAC) facilitate undruggable protein elimination. Here, functionalized fluorescent nanodiamond‐targeting chimera (FND‐TAC) reveals therapeutic protein clearance and tumor suppression through ENDOTAC linked to AUTOTAC networks. SQSTM1 is a key autophagy receptor mediating ENDOTAC linked to AUTOTAC for targeting protein degradation and cancer therapy. FND is a nanocarrier with stable fluorescence, enabling real‐time tracking of protein degradation and tumorigenesis. Pull‐down proteomics and STRING network analyses identified SQSTM1 as a central mediator linking Rab5/Rab7‐mediated FND endocytosis through ENDOTAC to AUTOTAC. Rab5/Rab7 ubiquitination, coordinated activation of the SQSTM1 PB1, LIR, and UBA domains, and SQSTM1 S403 phosphorylation through AUTOTAC enabled FND nanoparticulosome formation and subsequent nanoparticulophagy. Moreover, SQSTM1‐mediated LAMP1/2 organization linked AUTOTAC to LYTAC for lysosomal targeting. Functionalization with the therapeutic PD‐L1 monoclonal antibody atezolizumab (ATZ) to form FND‐ATZ demonstrated that ATZ‐targeted PD‐L1 was delivered to lysosomes for clearance and cancer cell death. Furthermore, FND‐ATZ highlighted therapeutic PD‐L1 clearance and tumor suppression through ENDOTAC linked to AUTOTAC networks. Real‐time observation of FND‐TAC reveals that ENDOTAC–AUTOTAC networks mediate therapeutic protein clearance and tumor inhibition.

An origami-based tactile sensory ring utilizing multilayered conductive paper substrates presents an innovative approach to wearable health applications. By harnessing paper’s flexibility and employing origami folding, the sensors integrate structural stability and self-packaging without added encapsulation layers. Knot-shaped designs create loop-based systems that secure conductive paper strips and protect sensing layers. Demonstrating a sensitivity of 3.8 kPa⁻¹ at subtle pressures (0–0.05 kPa), the sensors detect both minimal stimuli and high-pressure inputs. Electrical modeling of various origami configurations identifies designs with optimized performance with a pentagon knot offering higher sensitivity to support high-sensitivity needs. Meanwhile a square knot provides greater precision and quicker recovery, balancing sensitivity and stability for real-time feedback devices. The enhanced elastic modulus from folds remains within human skin’s elasticity range, ensuring comfort. Applications include grip strength monitoring and pulse rate detection from the thumb, capturing pulse transit time (PTT), an essential cardiovascular biomarker. This design shows the potential of origami-based tactile sensors in creating versatile, cost-effective wearable health monitoring systems.

Drawing inspiration from origami structures, a pressure sensor was developed with unique interconnection scaling at its creases crafted on a conductive paper substrate, paving the way for advanced wearable technology. Two screen-printed conductive paper substrates were combined face-to-face, and specific folds were introduced to optimize the sensor structure. The Electrical Contact Resistance (ECR) was systematically analyzed across different fold numbers and crease gaps, revealing a notable trade-off: while increasing the number of folds expanded the sensing area, it also influenced the ECR, reaching a performance plateau. Strategic modifications in the sensor's design, including refining interconnections at the crease, enhanced its sensitivity and stability, culminating in a remarkable sensitivity of 3.75 kPa^-1 at subtle pressure levels (0-0.05 kPa). This sensor's real-world applications proved to be transformative, from detecting bruxism and aiding in neck posture correction to remotely sensing trigger finger locking phenomena, highlighting its potential as a pivotal tool in upcoming medical diagnostics and treatments.

Selective autophagy is a defense mechanism by which foreign pathogens and abnormal substances are processed to maintain cellular homeostasis. Sequestosome 1 (SQSTM1)/p62, a vital selective autophagy receptor, recruits ubiquitinated cargo to form autophagosomes for lysosomal degradation. Nab-PTX is an albumin-bound paclitaxel nanoparticle used in clinical cancer therapy. However, the role of SQSTM1 in regulating the delivery and efficacy of nanodrugs remains unclear. Here we showed that SQSTM1 plays a crucial role in Nab-PTX drug delivery and efficacy in human lung and colorectal cancers. Nab-PTX induces SQSTM1 phosphorylation at Ser403, which facilitates its incorporation into the selective autophagy of nanoparticles, known as nanoparticulophagy. Nab-PTX increased LC3-II protein expression, which triggered autophagosome formation. SQSTM1 enhanced Nab-PTX recognition to form autophagosomes, which were delivered to lysosomes for albumin degradation, thereby releasing PTX to induce mitotic catastrophe and apoptosis. Knockout of SQSTM1 downregulated Nab-PTX-induced mitotic catastrophe, apoptosis, and tumor inhibition in vitro and in vivo and inhibited Nab-PTX-induced caspase 3 activation via a p53-independent pathway. Ectopic expression of SQSTM1 by transfection of an SQSTM1-GFP vector restored the drug efficacy of Nab-PTX. Importantly, SQSTM1 is highly expressed in advanced lung and colorectal tumors and is associated with poor overall survival in clinical patients. Targeting SQSTM1 may provide an important strategy to improve nanodrug efficacy in clinical cancer therapy. This study demonstrates the enhanced efficacy of Nab-PTX for human lung and colorectal cancers via SQSTM1-mediated nanodrug delivery.

Nanoprobes provide advantages for real-time monitoring of tumor markers and tumorigenesis during cancer progression and development. Epidermal growth factor receptor (EGFR) is a key protein that plays crucial roles for tumorigenesis and cancer therapy of lung cancers. Here, we show a carbon-based nanoprobe, nanodiamond (ND), which can be applied for targeting EGFR and monitoring tumorigenesis of human lung cancer cells in vitro and in vivo. The optimal fluorescent intensities of ND particles were observed in the human lung cancer cells and nude mice under in vivo imaging system. The fluorescence signal of ND particles can be real-time detected in the xenografted human lung tumor formation of nude mice. Moreover, the ND-conjugated specific EGFR antibody cetuximab (Cet) can track the location and distribution of EGFR proteins of lung cancer cells in vitro and in vivo. ND-Cet treatment increased cellular uptake ability of nanocomposites in the EGFR-expressed cells but not in the EGFR-negative lung cancer cells. Interestingly, single ND-Cet complex can be directly observed on the protein G bead by immunoprecipitation and confocal microscopy. Besides, the EGFR proteins were transported to lysosomes for degradation. Together, this study demonstrates that ND-conjugated Cet can apply for targeting EGFR and monitoring tumorigenesis during lung cancer progression and therapy.

It has been well studied that the surface topography affects the growth and development of neurons. However, the precise mechanism that the surface topography leads to cellular changes remains unknown. In this study, we created an anisotropic surface using nanodiamonds and discovered this surface topography accelerates the development of primary neurons from both the central and peripheral nervous systems. Using RNA sequencing technology, a previously uncharacterized microRNA (miR6236) was found to exhibit significant and the most substantial decrease when neurons are cultured on this nanodiamond surface. Gain- and loss-of-function assays confirm that miR6236 is the predominant molecule responsible for converting the surface topography into biological responses. We further demonstrate that the depletion of miR6236 can enhance neuroregeneration on inhibitory substrate, uncovering its therapeutic potential for promoting central nervous system regeneration.

Research attention has been given to selective autophagy due to its potential application in the pathophysiology of human diseases. The selective autophagy pathway contributes to the target recognition and degradation of intracellular components or foreign pathogens for maintaining cellular homeostasis in multiple organisms. Notably, this process is mediated by autophagy receptors in the recognition of autophagy cargoes through binding to the ubiquitin‐binding domain and LC3‐interacting region to the formation of autophagosomes. Nanotechnology is an emerging field; related research has focused on the study and manipulation of nanoscale materials that can be applied for numerous applications, especially for the diagnosis and treatment of human diseases. Nanoparticle‐mediated autophagy activation holds promise for use in autophagy‐related disease applications. The selective autophagy of nanoparticles and nanodrugs occurs through binding to ubiquitinated proteins, autophagy receptors, and LC3, the formation of nanoparticulosomes, and their delivery to lysosomes; the process is termed nanoparticulophagy. This review focuses on the mechanisms of nanoparticulophagy, the role of selective autophagy receptors, and potential applications in autophagy‐related diseases achieved using these nanoparticles and nanodrugs. Nanoparticulophagy will provide an understanding of related intracellular trafficking mechanisms and degradation pathways for processing nanoparticles and nanodrugs in terms of drug delivery and pathophysiological effects.