Photodynamic therapy (PDT) induces tumor cell pyroptosis, a form of programmed cell death that triggers antitumor immunity. However, high glucose metabolism and hypoxic conditions in the tumor microenvironment (TME) limit PDT efficiency and impair effector cell function. Here, we propose a cancer metabolic reprogramming-enabling photoresponsive nanoproteolysis-targeting chimera (Nano-PROTAC; NanoTAC), derived from the supramolecular self-assembly of drug conjugates that bridge a PROTAC targeting hexokinase II (HK2) and a photosensitizer via a biomarker-cleavable linker. In a triple-negative breast cancer (TNBC) model, NanoTAC initially silences PROTAC activity and accumulates in tumor regions, where it undergoes linker cleavage in response to enzymatic biomarkers. Upon photoirradiation, PDT-induced pyroptotic cell death promotes the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) to drive the cancer-immunity cycle. Concurrently, targeted protein degradation (TPD) via PROTACs counteracts glucose and oxygen consumption in the TME, ultimately potentiating pyroptosis-mediated photoimmunotherapy. This combination therapy achieves a high rate of complete regression in primary TNBC and confers adaptive immunity to prevent metastasis and recurrence. Our study presents a rationally designed nanomedicine that integrates PDT and PROTACs, shedding light on strategies for more effective cancer immunotherapy.

In light of the burgeoning successes of cancer immunotherapy, glioblastoma (GBM) remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity. Thus, identifying promising therapeutic targets for treating GBM and discovering methodologies to effectively regulate them is still a tremendous challenge. Here we describe photodynamic protein tyrosine phosphatase 1B (PTP1B) proteolysis mediated by a proteolysis-targeting chimera (PROTAC) nanoassembly. The PTP1B-targeting PROTAC is conjugated with a photosensitizer via a cathepsin B (Cat B)-cleavable peptide, which spontaneously forms nanoassemblies due to intermolecular π–π stacking interactions. In GBM models, PROTAC nanoassemblies significantly accumulate in the tumor region across the disrupted blood–brain barrier (BBB), triggering a burst release of the photosensitizer and active PROTAC by Cat B-mediated enzymatic cleavage. Upon laser irradiation, photodynamic therapy (PDT) synergizes with PROTAC-mediated PTP1B proteolysis to induce potent immunogenic cell death (ICD) in tumor cells. Subsequently, persistent PTP1B degradation by nanoassemblies in Cat B-overexpressed intratumoral T cells downregulates exhaustion markers, reinvigorating their functionality. These sequential processes of photodynamic PTP1B proteolysis ultimately augment T cell-mediated antitumor immunity as well as protective immunity, completely eradicating the primary GBM and preventing its recurrence. Overall, our findings underscore the therapeutic potential of combining PDT with PROTAC activity for GBM immunotherapy.

Low-molecular-weight heparin (LMWH), derived from unfractionated heparin (UFH), has enhanced anticoagulant efficacy, long duration of action, and extended half-life. Patients receiving LMWH for preventive therapies would strongly benefit from its long-term effects, however, achieving this is challenging. Here, we design and evaluate a nanoengineered LMWH and octadecylamine conjugate (LMHO) that can act for a long time while maintaining close to 97 ± 3% of LMWH activity via end-specific conjugation of the reducing end of LMWH. LMHO can self-assemble into nanoparticles with an average size of 105 ± 1.7 nm in water without any nanocarrier and can be combined with serum albumin, resulting in a lipid-based albumin shuttling effect. Such molecules can circulate in the bloodstream for 4–5 days. We corroborate the self-assembly capability of LMHO and its interaction with albumin through molecular dynamics (MD) simulations and transmission electron microscopy (TEM) analysis. This innovative approach to carrier-free polysaccharide delivery, enhanced by nanoengineered albumin shuttling, represents a promising platform to address limitations in conventional therapies.

Background: Fatty liver disease and obesity are among the most prevalent health conditions in modern society and have recently garnered significant attention. Semaglutide, a well-known anti-obesity drug, has been widely used for diabetes and obesity treatment; however, nanotherapeutics utilizing semaglutide have not yet been developed. Methods: A novel statin–lipid conjugate was synthesized using rosuvastatin and ursodeoxycholic acid, a liver-protective agent. This conjugate was then formulated with semaglutide through hydrophobic interactions to create a new nanoparticle system. The physicochemical properties of the nanoparticles were analyzed, and their therapeutic efficacy was evaluated in a high-fat diet (HFD)-induced animal model. Results: The statin–lipid conjugate was successfully synthesized, forming novel nanoparticles with semaglutide in an aqueous solution. These nanoparticles exhibited distinct properties compared to conventional semaglutide formulations. In animal experiments, the treatment group demonstrated a 30.24% reduction in body weight and a 46.80% improvement in liver function markers compared to the control group. Conclusions: This study introduces a novel semaglutide-based nanoparticle (SRLC NP) system that overcomes key limitations of conventional semaglutide therapy by providing enhanced bioavailability, extended circulation time, and improved cellular uptake. These findings highlight the potential of SRLC NPs as a clinically translatable nanotherapeutic approach for more effective, sustained, and patient-friendly obesity and fatty liver disease treatment.

In cancer therapy, photodynamic therapy (PDT) has attracted significant attention due to its high potential for tumor-selective treatment. However, PDT agents often exhibit poor physicochemical properties, including solubility, necessitating the development of nanoformulations. In this study, we developed two cationic peptide-based self-assembled nanomaterials by using a PDT agent, chlorin e6 (Ce6). To manufacture biocompatible nanoparticles based on peptides, we used the cationic poly-L-lysine peptide, which is rich in primary amines. We prepared low- and high-molecular-weight poly-L-lysine, and then evaluated the formation and performance of nanoparticles after chemical conjugation with Ce6. The results showed that both molecules formed self-assembled nanoparticles by themselves in saline. Interestingly, the high-molecular-weight poly-L-lysine and Ce6 conjugates (HPLCe6) exhibited better self-assembly and PDT performance than low-molecular-weight poly-L-lysine and Ce6 conjugates (LPLCe6). Moreover, the HPLCe6 conjugates showed superior cellular uptake and exhibited stronger cytotoxicity in cell toxicity experiments. Therefore, it is functionally beneficial to use high-molecular-weight poly-L-lysine in the manufacturing of poly-L-lysine-based self-assembling biocompatible PDT nanoconjugates.

The potential for polysaccharides to have long-term effects in the body is restricted by their naturally large molecular size and flexibility. In particular, patients receiving the anticoagulant heparin in preventive therapies would strongly benefit from an extended (long-term) effect of administered heparin, but the related technology has hardly been developed. Here, we have newly designed and evaluated a nanoengineered low-molecular-weight heparin (LMWH) and octadecylamine conjugate (LMHO) that can act for a long time while maintaining close to 97 ± 3% of heparin activity via end-specific conjugation of the reducing end of heparin. It generates self-assembled nanoparticles (NP) with an average size of 105 ± 1.7 nm in water without any nanocarrier and, further, can be combined with serum albumin, resulting in a lipid-based albumin shuttling effect such that the resulting molecules can circulate in the bloodstream for 4–5 days. We substantiate the self-assembly capability of LMHO and its interaction with albumin through molecular dynamics (MD) simulations and transmission electron microscopy (TEM) analysis, offering novel insights. This innovative approach to carrier-free polysaccharide delivery, enhanced by nanoengineered albumin shuttling, represents a promising platform to address limitations in conventional therapies.