Mou, C.-Y. | Search bioRxiv

bioRxiv2025

Antimetastatic Sulfonate-Functionalized Mesoporous Silica Nanoparticles Enhance Irinotecan Stability and Delivery for Colorectal Cancer Treatment

Metastatic colorectal cancer (mCRC) remains a leading cause of cancer-related mortality, with Irinotecan (IRI) serving as a backbone chemotherapeutic despite its dose-limiting toxicities, instability of the active lactone form, and lack of intrinsic antimetastatic activity. To overcome these barriers, we developed sulfonate-functionalized mesoporous silica nanoparticles (MSNs), referred to as (SO3-)-MSN-PEG/TA, as a multifunctional nanocarrier for IRI delivery. This nanoformulation markedly enhanced drug loading efficiency and preserved over 90% of the lactone form for up to six months, enabling sustained release and improved pharmacological stability. In vitro studies demonstrated superior cellular uptake, enhanced apoptosis, and a reduced IC50 compared to free IRI. Beyond drug delivery, (SO3-)-MSN-PEG/TA exhibited intrinsic antimetastatic activity by modulating focal adhesion kinase (FAK)/paxillin signaling, thereby impairing cell migration and suppressing angiogenesis, along with efficient tumor accumulation through the enhanced permeability and retention (EPR) effect. Pharmacokinetic analysis further revealed that IRI@(SO3-)-MSN-PEG/TA prolonged systemic retention, maintaining higher IRI plasma concentrations compared with free IRI. IRI@(SO3-)-MSN-PEG/TA significantly inhibited both primary tumor growth and metastatic dissemination in orthotopic and heterotopic colorectal cancer models, while markedly reducing systemic toxicities and preserving bone marrow cellularity relative to free IRI and liposomal IRI (Onivyde). Collectively, this dual-functional nanomedicine provides an innovative therapeutic strategy that not only augments IRI efficacy but also confers metastasis suppression and favorable pharmacokinetics, addressing critical unmet needs in mCRC treatment. These findings highlight the translational potential of IRI@(SO3-)-MSN-PEG/TA as a safer and more effective therapy for mCRC.

bioengineering↗

bioRxiv2025

Targeted Computational Design of an Interleukin-7 Superkine with Enhanced Folding Efficiency and Immunotherapeutic Efficacy

Interleukin-7 (IL-7) plays a central role in maintaining T cell development and immune homeostasis, and enhancing the cytokines immune-stimulatory functionality has broad therapeutic implications against various oncological malignancies. Herein, we show a computationally designed IL7 superkine, Neo-7, which exhibits enhanced folding efficiency and superior binding affinity to its cognate receptors. To streamline the protein candidate prediction and validation process, the loop region of IL7 was strategically targeted for redesign while most of the receptor-interacting regions were preserved. Leveraging advanced computational tools such as AlphaFold2, we show loop remodeling to rectify structural irregularities that allows for iterative stabilization of protein backbone and leads to identification of beneficial mutations conducive to receptor engagement. Neo-7 superkine shows improved thermostability and production yield, and it exhibits heightened immune-stimulatory and anticancer effect in C57BL/6J mice. These findings underscore the utility of a targeted computational approach for de novo cytokine development.

bioengineering↗