Carbon-Spaced Tandem-Disulfide Bond Bridge Design Addresses Limitations of Homodimer Prodrug Nanoassemblies: Enhancing Both Stability and Activatability.

Redox-responsive homodimer prodrug nanoassemblies (RHPNs) have emerged as a significant technology for overcoming chemotherapeutical limitations due to their high drug-loading capacity, low excipient-associated toxicity, and straightforward preparation method. Previous studies indicated that α-position disulfide bond bridged RHPNs exhibited rapid drug release rates but unsatisfactory assembly stability. In contrast, γ-disulfide bond bridged RHPNs showed better assembly stability but low drug release rates. Therefore, designing chemical linkages that ensure both stable assembly and rapid drug release remains challenging. To address this paradox of stable assembly and rapid drug release in RHPNs, we developed carbon-spaced double-disulfide bond (CSDD)-bridged RHPNs (CSDD-RHPNs) with two carbon-spaces. Pilot studies showed that CSDD-RHPNs with two carbon-spaces exhibited enhanced assembly stability, reduction-responsive drug release, and improved selective toxicity compared to α-/γ-position single disulfide bond bridged RHPNs. Based on these findings, CSDD-RHPNs with four and six carbon-spaces were designed to further investigate the properties of CSDD-RHPNs. These CSDD-RHPNs exhibited excellent assembly ability, safety, and prolonged circulation. Particularly, CSDD-RHPNs with two carbon-spaces displayed the best antitumor efficacy on 4T1 and B16-F10 tumor-bearing mice. CSDD chemical linkages offer novel perspectives on the rational design of RHPNs, potentially overcoming the design limitations regarding contradictory assembly ability and drug release rate.

Boarding pyroptosis onto nanotechnology for cancer therapy.

Pyroptosis, a non-apoptotic programmed cellular inflammatory death mechanism characterized by gasdermin (GSDM) family proteins, has gathered significant attention in the cancer treatment. However, the alarming clinical trial data indicates that pyroptosis-mediated cancer therapeutic efficiency is still unsatisfactory. It is essential to integrate the burgeoning biomedical findings and innovations with potent technology to hasten the development of pyroptosis-based antitumor drugs. Considering the rapid development of pyroptosis-driven cancer nanotherapeutics, here we aim to summarize the recent advances in this field at the intersection of pyroptosis and nanotechnology. First, the foundation of pyroptosis-based nanomedicines (NMs) is outlined to illustrate the reliability and effectiveness for the treatment of tumor. Next, the emerging nanotherapeutics designed to induce pyroptosis are overviewed. Moreover, the cross-talk between pyroptosis and other cell death modalities are discussed, aiming to explore the mechanistic level relationships to provide guidance strategies for the combination of different types of antitumor drugs. Last but not least, the opportunities and challenges of employing pyroptosis-based NMs in potential clinical cancer therapy are highlighted.

52 Gbps PAM4 receiver sensitivity study for 400GBase-LR8 system using directly modulated laser.

Real-time 52 Gbps PAM4 transmission is demonstrated over single mode fiber (SMF) using a directly modulated laser (DML) and a PHY chip. The inner eye optical modulation amplitude (OMA) receiver sensitivities were measured and compared using avalanche photodetector (APD) and PIN photodetector (PD) for the maximum and minimum chromatic dispersions (CDs) of 400GBase-LR8 link. The measured inner eye OMAs were -17.8 dBm and -18.8 dBm for + 10 ps/nm and -58 ps/nm of CDs at the KP4 bit error rate (BER) threshold of 2 × 10-4 using a PIN PD, respectively. The measured inner eye OMA was improved to -21.0 dBm for -58 ps/nm of CD at the KP4 BER threshold using an APD. Negligible OMA penalty (< 0.4 dB) was captured for operating DML at different bias currents of 40 mA and 60 mA using a PIN PD and an APD for both positive and negative CDs at the KP4 BER threshold.