Glioblastoma (GBM) interventions necessitate exceptional precision due to the presence of blood-brain barrier (BBB) and its intricate co-growth with neuron and glial cells. Here, we developed a blocked bioorthogonal chemistry enabled liposome, termed Bioorthosome, with switchable BBB-crossing ligand that could block the bioorthogonal moieties in normal tissue and blood circulation. Upon traversing the BBB and reaching tumor region, the BBB-crossing ligand could detach from the Bioorthosome under acidic tumor microenvironment and switch to the bioorthogonal moieties to react with the metabolically expressed azide-containing sialylations on GBM cell surface. This switchable bioorthogonal chemistry ensures that only GBM cells are targeted, thereby enhancing the precision of liposomal drug delivery. In vitro and in vivo studies have demonstrated that the Bioorthosome efficiently crosses the BBB and undergoes a ligand-switching process to selectively recognize GBM cells while sparing normal brain tissue, leading to enhanced therapeutic efficacy and reduced off-target accumulation. By integrating bioorthogonal reactions with a tumor microenvironment-responsive ligand-switching mechanism, our Bioorthosome design overcomes the limitations of inefficient BBB permeability and suboptimal anti-GBM drug delivery, paving the way for more precise GBM-targeted therapies and the advancement of more effective treatment strategies.

Although anti-cancer nanotherapeutics have made breakthroughs, many remain clinically unsatisfactory due to limited delivery efficiency and complicated biological barriers. Here, we prepared charge-reversible crosslinked nanoparticles (PDC NPs) by supramolecular self-assembly of pro-apoptotic peptides and photosensitizers, followed by crosslinking the self-assemblies with polyethylene glycol to impart tumor microenvironment responsiveness and charge-reversibility. The resultant PDC NPs have a high drug loading of 68.3%, substantially exceeding that of 10%–15% in conventional drug delivery systems. PDC NPs can overcome the delivery hurdles to significantly improve the tumor accumulation and endocytosis of payloads by surface charge reversal and responsive crosslinking strategy. Pro-apoptotic peptides target the mitochondrial membranes and block the respiratory effect to reduce local oxygen consumption, which extensively augments oxygen-dependent photodynamic therapy (PDT). The photosensitizers around mitochondria increased along with the peptides, allowing PDT to work with pro-apoptotic peptides synergistically to induce tumor cell death by mitochondria-dependent apoptotic pathways. Our strategy would provide a valuable reference for improving the delivery efficiency of hydrophilic peptides and developing mitochondrial-targeting cancer therapies.

Nanoprodrugs that are directly assembled by prodrugs attract considerable attention with high anticancer potentials. However, their stability and efficiency of tumor-targeted delivery remain a major challenge in practical biomedical applications. Here, we report a new deep tumor-penetrating nano-delivery strategy to achieve enhanced anti-cancer performance by systematic optimization of a porphyrin-doxorubicin-based nanoprodrug using various PEGylations/crosslinks and co-administration of targeting peptide iRGD. Polyethylene glycols (PEGs) with different molecular weights and grafts are employed to crosslink the nanoprodrug and optimize size, charge, tumor accumulation and penetration, and anti-cancer efficiency, etc. The tumor penetration was validated in syngeneic oral cancer mouse models, patient-derived xenograft (PDX) models, and oral cancer tissue from patients. The optimized nanoprodrug co-administrated with iRGD remarkably enhances the accumulation and penetration both in tumor vascular and PDX tumor tissue. It is effective and safe to improve in vivo therapeutic efficacy via the passive tumor targeting dependent and independent mode. Our tumor-penetrating nano-delivery strategy is promising to strengthen the nanoprodrugs in clinical implementation.