Glioma is the most common primary malignant tumor of the central nervous system. Despite traditional treatments such as surgical resection, combined postoperative chemotherapy, and radiotherapy, it remains challenging to significantly improve the long-term survival rate of patients. This is primarily due to the incomplete surgical removal of the tumor and its resistance to radiotherapy. Boron neutron capture therapy (BNCT) is a novel radiotherapy that can selectively kill tumor cells. Current research has demonstrated that BNCT offers effective local disease control for gliomas and head and neck tumors. However, the existing boron-containing drugs are still unsatisfactory due to their low boron content and poor targeting ability. The synergistic treatment has provided new ideas for the development of BNCT, and the emergence of nanosystems offers the possibility of prolonged retention and pinpoint delivery of boron drugs in the tumor. The unique tumor microenvironment(TME) of gliomas, characterized by the blood brain barrier (BBB), oxidative stress, hypoxia and angiogenesis, renders conventional treatments ineffective and poor prognosis. Therefore, to combine the TME regulation and BNCT, we prepared a stable nanosystem in this study. It is a borane-contained cationic liposome modified with cRGD peptide which enhances the tumor-targeting ability. And the enzymes Lactate oxidase(LOX) and Catalase(CAT) are absorbed on the surface of the nanosystem which reduce the concentration of lactic acid through a cascade reaction to generate O₂ and decrease the protein expression level of HIF-1α. This nanosystem exhibited a more potent anti-tumor effect both in vitro and in vivo. Also it reduced tumor stemness in vivo, which improves the prognosis. Therefore, the novel nanosystem combined microenvironment regulation therapy and BNCT shows the great potential application in anti-tumor treatment.

Traditionally, hyaluronic acid has been widely used for drug delivery, but the current application bottleneck is that hyaluronic acid is hydrophilic and electronegative, which makes it difficult to carry hydrophobic drugs and small interfering RNA (siRNA) with the same charge. Based on previous studies, we designed and synthesized hyaluronic acid nanocarriers HA-spermine/N,N,N-trimethylcystamine/DOX-TPP (HSTD) for loading siRNA to overcome the problem of siRNA release caused by strong electrostatic interaction. Then, N,N,N-trimethylcystamine in the carrier can be degraded by intracellular glutathione to completely and rapidly release siRNA, thus promoting transfection. Moreover, when co-delivered with the chemotherapy drug doxorubicin (DOX), this novel nanocarrier showed promising synergy in inhibiting tumor growth.

Orally administered peptides or proteins are garnering increasing preference owing to their superiority in terms of patient compliance and convenience. However, the development of oral protein formulations has stalled due to the low bioavailability of macromolecules that encounter the aggressive gastrointestinal environment and harsh mucus villi barrier. Herein, we propose an ideal reverse micelle/self-emulsifying drug delivery system (RM/SEDDS) nanoplatform that is capable of improving the oral bioavailability of hydrophilic peptides by preventing enzymatic degradation and enhancing mucosal permeability. Upon the passage through the mucus, the self-emulsifying drug delivery system with optimal surface properties effectively penetrates the viscoelastic mucosal barrier, followed by the exposure of the inner reverse micelle amphipathic vectors, which autonomously form continua with the lipidic cell membrane and facilitate the internalization of drugs. This membrane-fusion mechanism inaugurates a new way for hydrophilic peptide delivery in the free form, circumventing the traditional impediments of the cellular internalization of nanocarriers and subsequent poor release of drugs. And more importantly, reverse micelles are not spatially specific to the laden drugs, which enables their delivery for a myriad of peptide clinical drugs. In conclusion, as an exquisitely designed nanoplatform, RM/SEDDS overcomes multiple physiological barriers and opens a new path for drug cellular entry, providing new prospects for the development of oral drug delivery systems.