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.

Epidermal growth factor receptor (EGFR)-targeted therapeutics, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), have achieved clinical success but are limited by drug resistance and off-target toxicity. Herein, self-assembling peptide-derived PROTAC nanoparticles (NanoTACs) engineered for effective degradation of both wild-type and mutant EGFR for cancer therapy is reported. The NanoTACs are constructed from three peptide components: EGFR-binding peptide (EHGAMEI), a self-assembling peptide linker (FF), and an E3 ligase recruiting peptide (ALAPYIP). Through the hydrophobic interaction and π-π stacking, self-assembling peptide-derived PROTACs formed uniform spherical nanoparticles with an average diameter of 144 nm under aqueous conditions. In vitro, NanoTACs effectively eliminated both wild-type and L858R/T790M-mutant EGFR in cancer cells through direct lysosomal degradation and PROTAC-driven proteasomal degradation. In vivo, NanoTACs exhibited 2.24-fold higher tumor-targeting efficiency than free EGFR-binding peptide via the enhanced permeability and retention (EPR) effect and EGFR-mediated active targeting. In colon and lung tumor models, NanoTACs suppressed tumor growth by 88.3%, achieved 95% degradation of wild-type and 80% of mutant EGFR, and induced extensive apoptosis without systemic toxicity. These findings established NanoTACs as a promising EGFR-targeted platform to overcome drug resistance to mAbs and TKIs by enabling effective degradation of wild-type and mutant EGFR in heterogeneous cancers.

While proteolysis-targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment via targeted protein degradation, precisely activating them in tumor tissues and preventing uncontrolled proteolysis at off-target sites remain challenging. Herein, a light-triggered PROTAC nanoassembly (LPN) for photodynamic indoleamine 2,3-dioxygenase (IDO) proteolysis is reported. The LPN is derived from the self-assembly of prodrug conjugates, which comprise a PROTAC, cathepsin B-specific cleavable peptide linker, and photosensitizer, without any additional carrier materials. In colon tumor models, intravenously injected LPNs initially silence the activity of PROTACs and accumulate significantly in targeted tumor tissues due to an enhanced permeability and retention effect. Subsequently, the cancer biomarker cathepsin B begins to trigger the release of active PROTACs from the LPNs through enzymatic cleavage of the linkers. Upon light irradiation, tumor cells undergo immunogenic cell death induced by photodynamic therapy to promote the activation of effector T cells, while the continuous IDO degradation of PROTAC simultaneously blocks tryptophan metabolite-regulated regulatory-T-cell-mediated immunosuppression. Such LPN-mediated combinatorial photodynamic IDO proteolysis effectively inhibits tumor growth, metastasis, and recurrence. Collectively, this study presents a promising nanomedicine, designed to synergize PROTACs with other immunotherapeutic modalities, for more effective and safer cancer immunotherapy.

Cancer Immunotherapy Man Kyu Shim, Yongju Kim, Yoosoo Yang, and colleagues develope a light-triggered proteolysis-targeting chimera (PROTAC) nanoassembly. This nanoassembly accumulates significantly in tumor tissues, triggering a burst release of active PROTACs. Upon light irradiation, tumor cells undergo immunogenic cell death to promote T cell activation, while the recyclable action of the PROTACs simultaneously blocks regulatory T cell-mediated immunosuppression. More details can be found in article number 2405475.

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.

Epidermal growth factor receptor (EGFR)-targeted therapeutics, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), have achieved clinical success but are limited by drug resistance and off-target toxicity. Herein, self-assembling peptide-derived PROTAC nanoparticles (NanoTACs) engineered for effective degradation of both wild-type and mutant EGFR for cancer therapy is reported. The NanoTACs are constructed from three peptide components: EGFR-binding peptide (EHGAMEI), a self-assembling peptide linker (FF), and an E3 ligase recruiting peptide (ALAPYIP). Through the hydrophobic interaction and π-π stacking, self-assembling peptide-derived PROTACs formed uniform spherical nanoparticles with an average diameter of 144 nm under aqueous conditions. In vitro, NanoTACs effectively eliminated both wild-type and L858R/T790M-mutant EGFR in cancer cells through direct lysosomal degradation and PROTAC-driven proteasomal degradation. In vivo, NanoTACs exhibited 2.24-fold higher tumor-targeting efficiency than free EGFR-binding peptide via the enhanced permeability and retention (EPR) effect and EGFR-mediated active targeting. In colon and lung tumor models, NanoTACs suppressed tumor growth by 88.3%, achieved 95% degradation of wild-type and 80% of mutant EGFR, and induced extensive apoptosis without systemic toxicity. These findings established NanoTACs as a promising EGFR-targeted platform to overcome drug resistance to mAbs and TKIs by enabling effective degradation of wild-type and mutant EGFR in heterogeneous cancers.

While proteolysis-targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment via targeted protein degradation, precisely activating them in tumor tissues and preventing uncontrolled proteolysis at off-target sites remain challenging. Herein, a light-triggered PROTAC nanoassembly (LPN) for photodynamic indoleamine 2,3-dioxygenase (IDO) proteolysis is reported. The LPN is derived from the self-assembly of prodrug conjugates, which comprise a PROTAC, cathepsin B-specific cleavable peptide linker, and photosensitizer, without any additional carrier materials. In colon tumor models, intravenously injected LPNs initially silence the activity of PROTACs and accumulate significantly in targeted tumor tissues due to an enhanced permeability and retention effect. Subsequently, the cancer biomarker cathepsin B begins to trigger the release of active PROTACs from the LPNs through enzymatic cleavage of the linkers. Upon light irradiation, tumor cells undergo immunogenic cell death induced by photodynamic therapy to promote the activation of effector T cells, while the continuous IDO degradation of PROTAC simultaneously blocks tryptophan metabolite-regulated regulatory-T-cell-mediated immunosuppression. Such LPN-mediated combinatorial photodynamic IDO proteolysis effectively inhibits tumor growth, metastasis, and recurrence. Collectively, this study presents a promising nanomedicine, designed to synergize PROTACs with other immunotherapeutic modalities, for more effective and safer cancer immunotherapy.

Cancer Immunotherapy Man Kyu Shim, Yongju Kim, Yoosoo Yang, and colleagues develope a light-triggered proteolysis-targeting chimera (PROTAC) nanoassembly. This nanoassembly accumulates significantly in tumor tissues, triggering a burst release of active PROTACs. Upon light irradiation, tumor cells undergo immunogenic cell death to promote T cell activation, while the recyclable action of the PROTACs simultaneously blocks regulatory T cell-mediated immunosuppression. More details can be found in article number 2405475.

Nanomedicine is the biomedical application of nanoscale materials for diagnosis and therapy of disease. Recent advances in nanotechnology and biotechnology have contributed to the development of multifunctional nanoparticles as representative nanomedicine. They were initially developed to enable the target-specific delivery of imaging or therapeutic agents for biomedical applications. Due to their unique features including multifunctionality, large surface area, structural diversity, and long circulation time in blood compared to small molecules, nanoparticles have emerged as attractive preferences for optimized therapy through personalized medicine. Multimodal imaging and theragnosis are the cutting-edge technologies where the advantages of nanoparticles are maximized. Because each imaging modality has its pros and cons, the integration of several imaging agents with different properties into multifunctional nanoparticles allows precise and fast diagnosis of disease through synergetic multimodal imaging. Moreover, nanoparticles are not only used for molecular imaging but also applied to deliver therapeutic agents to the disease site in order to accomplish the simultaneous imaging and therapy called theragnosis. This tutorial review will highlight the recent advances in the development of multifunctional nanoparticles and their biomedical applications to multimodal imaging and theragnosis as nanomedicine.

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 <i>via</i> a cathepsin B (Cat B)-cleavable peptide, which spontaneously forms nanoassemblies due to intermolecular <i>π</i>-<i>π</i> 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.

Doxorubicin (DOX) is a potent anticancer drug, but its poor tumor selectivity and systemic toxicity limit clinical use and hinder cancer immunotherapy despite its ability to induce immunogenic cell death (ICD). To overcome these limitations, we developed self-assembling, cathepsin B-cleavable peptide (Phe-Arg-Arg-X: FRRX)-DOX prodrugs forming nanoparticles via hydrophobic and π-π interactions. Among them, the FRRL-DOX nanoparticles (cathepsin B-cleavable DOX prodrug nanoparticles; CatB-NPs) exhibited stable nanoparticle structure with an average diameter of 165.1 ± 24.7 nm and enhanced tumor accumulation through the enhanced permeation and retention (EPR) effect. In the cell culture systems, CatB-NPs showed the cancer cell-specific ICD while minimizing non-specific damage to normal cells and immune cells. In the CT26 tumour-bearing mice, CatB-NPs exhibited improved pharmacokinetics, enhanced tumor accumulation, and significantly greater therapeutic efficacy. When combined with anti-PD-L1 antibody, CatB-NPs achieved 100% complete tumor regression, with elevated dendritic cell (DC) activation, cytotoxic T cell infiltration, and durable immunological memory. Furthermore, CatB-NPs greatly reduced the cardiotoxicity and splenic toxicity associated with free DOX, preserving tissue structure and immune function. This study highlights the clinical potential of self-assembling and cathepsin B-cleavable prodrug nanoparticles as a next-generation anticancer drug with improved safety and immune compatibility.

High-dose chemotherapy exhibits potent therapeutic efficacy in pancreatic cancer. However, its application is often limited because of severe toxicity and drug resistance. Herein, a high-dose therapy of pro-apoptotic doxorubicin (DOX) prodrug-encapsulated PEGylated liposomes (Aposomes) is presented for the treatment of pancreatic cancer. The prodrug is synthesized by conjugating DOX with a second mitochondria-derived activator of caspases mimetic peptide (SMAC-P-FRRL; AVPIAQ-FRRL: antagonist of inhibitor of apoptosis proteins), in which the cathepsin B-cleavable -RR- sequence enables selective release. The resulting SMAC-P-FRRL-DOX is efficiently encapsulated into PEGylated liposomes (87.7 ± 0.48 nm), which induced apoptosis specifically in cathepsin B-overexpressing pancreatic cancer cells. In KPC960 tumor-bearing mice, repeated administration of high-dose Aposomes facilitates preferential tumor accumulation via the enhanced permeability and retention (EPR) effect and exerts potent antitumor activity with minimal toxicity in normal tissues. Moreover, the therapeutic efficacy and safety profile of high-dose Aposomes are validated in humanized NOD scid gamma (NSG) mice. Notably, high-dose Aposomes significantly reduce orthotopic pancreatic tumor size in NSG mice without toxicity in the blood, immune system, and normal tissues. This high-dose therapy of Aposomes can greatly improve the therapeutic index of pancreatic cancer chemotherapy without causing severe toxicity and potential drug resistance.