In situ sustained release hydrogel system delivering GLUT1 inhibitor and chemo-drug for cancer post-surgical treatment.

Systematic administration of small molecular drugs often suffered from the low efficacy and systemic toxicity in cancer therapy. In addition, application of single mode drug usually leads to unsatisfactory therapeutic outcomes. Currently, developing multimodal-drug combination strategy that acts on different pathways without increasing side effects remains great challenge. Here, we developed a hydrogel system that co-delivered glycolysis inhibitor apigenin and chemo-drug gemcitabine to realize combination strategy for combating cancer with minimal systemic toxicity. We demonstrated that this system can not only eliminate tumor cells in situ, but also induce abscopal effect on various tumor models. These results showed that our study provided a safe and effective strategy for clinical cancer treatment.

Spatiotemporal release of non-nucleotide STING agonist and AKT inhibitor from implantable 3D-printed scaffold for amplified cancer immunotherapy.

Immunotherapy through the activation of the stimulator of interferon genes (STING) signaling pathway is increasingly recognized for its robust anti-tumor efficacy. However, the effectiveness of STING activation is often compromised by inadequate anti-tumor immunity and a scarcity of primed immune cells in the tumor microenvironment. Herein, we design and fabricate a co-axial 3D-printed scaffold integrating a non-nucleotide STING agonist, SR-717, and an AKT inhibitor, MK-2206, in its respective shell and core layers, to synergistically enhance STING activation, thereby suppressing tumor recurrence and growth. SR-717 initiates the STING activation to enhance the phosphorylation of the factors along the STING pathway, while MK-2206 concurrently inhibits the AKT phosphorylation to facilitate the TBK1 phosphorylation of the STING pathway. The sequential and sustained release of SR-717 and MK-2206 from the scaffold results in a synergistic STING activation, demonstrating substantial anti-tumor efficacy across multiple tumor models. Furthermore, the scaffold promotes the recruitment and enrichment of activated dendritic cells and M1 macrophages, subsequently stimulating anti-tumor T cell activity, thereby amplifying the immunotherapeutic effect. This precise and synergistic activation of STING by the scaffold offers promising potential in tumor immunotherapy.

A LIGHTFUL nanomedicine overcomes EGFR-mediated drug resistance for enhanced tyrosine-kinase-inhibitor-based hepatocellular carcinoma therapy.

Targeting the activated epidermal growth factor receptor (EGFR) via clustered regularly interspaced short palindromic repeat (CRISPR) technology is appealing to overcome the drug resistance of hepatocellular carcinoma (HCC) towards tyrosine kinase inhibitor (TKI) therapy. However, combining these two distinct drugs using traditional liposomes results in a suboptimal synergistic anti-HCC effect due to the limited CRISPR/Cas9 delivery efficiency caused by lysosomal entrapment after endocytosis. Herein, we developed a liver-targeting gene-hybridizing-TKI fusogenic liposome (LIGHTFUL) that can achieve high CRISPR/Cas9 expression to reverse the EGFR-mediated drug resistance for enhanced TKI-based HCC therapy efficiently. Coated with a galactose-modified membrane-fusogenic lipid layer, LIGHTFUL reached the targeting liver site to fuse with HCC tumor cells, directly and efficiently transporting interior CDK5- and PLK1-targeting CRISPR/Cas9 plasmids (pXG333-CPs) into the HCC cell cytoplasm and then the cell nucleus for efficient expression. Such membrane-fusion-mediated pXG333-CP delivery resulted in effective downregulation of both CDK5 and PLK1, sufficiently inactivating EGFR to improve the anti-HCC effects of the co-delivered TKI, lenvatinib. This membrane-fusion-participant codelivery strategy optimized the synergetic effect of CRISPR/Cas9 and TKI combinational therapy as indicated by the 0.35 combination index in vitro and the dramatic reduction of subcutaneous and orthotopic TKI-insensitive HCC tumor growth in mice. Therefore, the established LIGHTFUL provides a unique co-delivery platform to combine gene editing and TKI therapies for enhanced synergetic therapy.

Development of stimuli responsive polymeric nanomedicines modulating tumor microenvironment for improved cancer therapy.

The complexity of the tumor microenvironment (TME) severely hinders the therapeutic effects of various cancer treatment modalities. The TME differs from normal tissues owing to the presence of hypoxia, low pH, and immune-suppressive characteristics. Modulation of the TME to reverse tumor growth equilibrium is considered an effective way to treat tumors. Recently, polymeric nanomedicines have been widely used in cancer therapy, because their synthesis can be controlled and they are highly modifiable, and have demonstrated great potential to remodel the TME. In this review, we outline the application of various stimuli responsive polymeric nanomedicines to modulate the TME, aiming to provide insights for the design of the next generation of polymeric nanomedicines and promote the development of polymeric nanomedicines for cancer therapy.

Implantable 3D Printed Hydrogel Scaffolds Loading Copper-Doxorubicin Complexes for Postoperative Chemo/Chemodynamic Therapy.

Biomaterial-based implants hold great potential for postoperative cancer treatment due to the enhanced drug dosage at the disease site and decreased systemic toxicity. However, the elaborate design of implants to avoid complicated chemical modification and burst release remains challenging. Herein, we report a three-dimensional (3D) printed hydrogel scaffold to enable sustained release of drugs for postoperative synergistic cancer therapy. The hydrogel scaffold is composed of Pluronic F127 and sodium alginate (SA) as well as doxorubicin (DOX) and copper ions (F127-SA/Cu-DOX hydrogel scaffold). Benefiting from the coordination of Cu(II) with both SA and DOX, burst release of DOX can be overcome, and prolonged release time can be achieved. The therapeutic efficiency can be adjusted by altering the amount of DOX and Cu(II) in the scaffolds. Moreover, apoptosis and ferroptosis of cancer cells can be induced through the combination of chemotherapy and chemodynamic therapy. In addition, DOX supplies excess hydrogen peroxide to enhance the efficiency of Cu-based chemodynamic therapy. When implanted in the resection site, hydrogel scaffolds effectively inhibit tumor growth. Overall, this study may offer a new strategy for fabricating local implants with synergistic therapeutic performance for preventing postoperative cancer recurrence.

Self-intensified synergy of a versatile biomimetic nanozyme and doxorubicin on electrospun fibers to inhibit postsurgical tumor recurrence and metastasis.

Tumor-positive resection margins after surgery can result in tumor recurrence and metastasis. Although adjuvant postoperative radiotherapy and chemotherapy have been adopted in clinical practice, they lack efficacy and result in unavoidable side effects. Herein, a self-intensified in-situ therapy approach using electrospun fibers loaded with a biomimetic nanozyme and doxorubicin (DOX) is developed. The fabricated PEG-coated zeolite imidazole framework-67 (PZIF67) is demonstrated as a versatile nanozyme triggering reactions in cancer cells based on endogenous H2O2 and •O2-. The PZIF67-generated •OH induces reactive oxygen species (ROS) overload, implementing chemodynamic therapy (CDT). The O2 produced by PZIF67 inhibits the expression of hypoxia-up-regulated proteins, thereby suppressing tumor progression. PZIF67 also catalyzes the degradation of glutathione, further disturbing the intracellular redox homeostasis and enhancing CDT. Furthermore, the introduced DOX not only kills cancer cells individually, but also replenishes the continuously consumed substrates for PZIF67-catalyzed reactions. The PZIF67-weakened drug resistance strengthens the cytotoxicity of DOX. The combined application of PZIF67 and DOX also suppresses metastasis-associated genes. Both in vitro and in vivo results demonstrate that the self-intensified synergy of PZIF67 and DOX on electrospun fibers efficiently prevents postsurgical tumor recurrence and metastasis, offering a feasible therapeutic regimen for operable malignant tumors.

Recent advances in nanomaterials for prostate cancer detection and diagnosis.

Despite the significant progress in the discovery of biomarkers and the exploitation of technologies for prostate cancer (PCa) detection and diagnosis, the initial screening of these PCa-related biomarkers using current technologies is always demanded with a bioassay or probe with high sensitivity, specificity, and noninvasiveness. Nanomaterials have emerged as novel alternative probes for PCa detection and diagnosis because of their nanoscale size, large ratio of surface area to volume, special surface chemistry, and particularly distinct physical properties. By selecting appropriate nanomaterials, a series of nanosensors or nanoprobes could be constructed for PCa bioassay with high sensitivity, selectivity, and accuracy. Meanwhile, nanosized particles also show significant potential to transport directors or contrast agents to desired sites in vivo for accurate and safe visualization of PCa tissues. Based on these advancements, this review will first outline the recent exploration of PCa biomarkers and the development of technologies for clinical PCa diagnosis. Then, the commonly used nanomaterials for PCa detection and diagnosis will be summarized. Finally, the current challenges and prospects of nanoparticle-based PCa detection and diagnosis methods are also discussed.

3D printed hydrogel scaffolds combining glutathione depletion-induced ferroptosis and photothermia-augmented chemodynamic therapy for efficiently inhibiting postoperative tumor recurrence.

Surgical resection to achieve tumor-free margins represents a difficult clinical scenario for patients with hepatocellular carcinoma. While post-surgical treatments such as chemotherapy and radiotherapy can decrease the risk of cancer recurrence and metastasis, growing concerns about the complications and side effects have promoted the development of implantable systems for locoregional treatment. Herein, 3D printed hydrogel scaffolds (designed as Gel-SA-CuO) were developed by incorporating one agent with multifunctional performance into implantable devices to simplify the fabrication process for efficiently inhibiting postoperative tumor recurrence. CuO nanoparticles can be effectively controlled and sustained released during the biodegradation of hydrogel scaffolds. Notably, the released CuO nanoparticles not only function as the reservoir for releasing Cu2+ to produce intracellular reactive oxygen species (ROS) but also serve as photothermal agent to generate heat. Remarkably, the heat generated by photothermal conversion of CuO nanoparticles further promotes the efficiency of Fenton-like reaction. Additionally, ferroptosis can be induced through Cu2+-mediated GSH depletion via the inactivation of GPX4. By implanting hydrogel scaffolds in the resection site, efficient inhibition of tumor recurrence after primary resection can be achieved in vivo. Therefore, this study may pave the way for the development of advanced multifunctional implantable platform for eliminating postoperative relapsable cancers.

Implantable Sandwich-like Scaffold/Fiber Composite Spatiotemporally Releasing Combretastatin A4 and Doxorubicin for Efficient Inhibition of Postoperative Tumor Recurrence.

Tumor recurrence is a critical conundrum in the postoperative therapy, on account of severe bleeding with disseminated tumor cells, residual tumor cells, and the rich nutrient and oxygen supply transported to tumors by the abundant blood vessels. Biodegradable drug-loaded implants, inserted in the resection cavity right away upon the surgery, possess bleeding prevention and efficient chemotherapeutic capabilities, considered to be a promising strategy to efficiently inhibit the recurrence of the solid tumor. Here, we developed a sandwich-like composite consisting of the combretastatin A4 (CA4)-loaded 3D-printed scaffold and doxorubicin (DOX)-loaded electrospun fiber (Scaffold-CA4@Fiber-DOX), presenting hemostatic, chemotherapeutic, and antibacterial potencies. The lyophilized 3D-printed scaffold with a porous structure rapidly absorbed and clotted the blood cells and disseminated tumor cells to prevent bleeding and tumor metastasis. Subsequently, the preferentially released CA4 from the scaffold disrupted the microtubules of the vascular endothelial cell, resulting in vascular deformation and consequent insufficient nutrient supply to the solid tumor. The sustained release of DOX from the sandwiched electrospun fiber dramatically inhibited the peripheral tumor cell proliferation. This all-in-one multifunctional implant system, combining efficient vascular disruption and chemotherapy, provides a promising strategy for postoperative tumor therapy.

Well-Defined Mannosylated Polymer for Peptide Vaccine Delivery with Enhanced Antitumor Immunity.

Peptide-based cancer vaccines offer production and safety advantages but have had limited clinical success due to their intrinsic instability, rapid clearance, and low cellular uptake. Nanoparticle-based delivery vehicles can improve the in vivo stability and cellular uptake of peptide antigens. Here, a well-defined, self-assembling mannosylated polymer is developed for anticancer peptide antigen delivery. The amphiphilic polymer is prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization, and the peptide antigens are conjugated to the pH-sensitive hydrophobic block through the reversible disulfide linkage for selective release after cell entry. The polymer-peptide conjugates self-assemble into sub-100 nm micelles at physiological pH and dissociate at endosomal pH. The mannosylated micellar corona increases the accumulation of vaccine cargoes in the draining inguinal lymph nodes and facilitates nanoparticle uptake by professional antigen presenting cells. In vivo studies demonstrate that the mannosylated micelle formulation improves dendritic cell activation and enhances antigen-specific T cell responses, resulting in higher antitumor immunity in tumor-bearing mice compared to free peptide antigen. The mannosylated polymer is therefore a simple and promising platform for the delivery of peptide cancer vaccines.

Engineering Nano-Therapeutics to Boost Adoptive Cell Therapy for Cancer Treatment.

Although adoptive transfer of therapeutic cells to cancer patients is demonstrated with great success and fortunately approved for the treatment of leukemia and B-cell lymphoma, potential issues, including the unclear mechanism, complicated procedures, unfavorable therapeutic efficacy for solid tumors, and side effects, still hinder its extensive applications. The explosion of nanotechnology recently has led to advanced development of novel strategies to address these challenges, facilitating the design of nano-therapeutics to improve adoptive cell therapy (ACT) for cancer treatment. In this review, the emerging nano-enabled approaches, that design multiscale artificial antigen-presenting cells for cell proliferation and stimulation in vitro, promote the transducing efficiency of tumor-targeting domains, engineer therapeutic cells for in vivo imaging, tumor infiltration, and in vivo functional sustainability, as well as generate tumoricidal T cells in vivo, are summarized. Meanwhile, the current challenges and future perspectives of the nanostrategy-based ACT for cancer treatment are also discussed in the end.

Development of D-melittin polymeric nanoparticles for anti-cancer treatment.

Melittin, the primary peptide component of bee venom, is a potent cytolytic anti-cancer peptide with established anti-tumor activity. However, practical application of melittin in oncology is hampered by its strong, nonspecific hemolytic activity and intrinsic instability. To address these shortcomings, delivery systems are used to overcome the drawbacks of melittin and facilitate its safe delivery. Yet, a recent study revealed that encapsulated melittin remains immunogenic and can act as an adjuvant to elicit a fatal antibody immune response against the delivery carrier. We discovered that substitution of l-amino acids with d-amino acids mitigates this problem: D-melittin nanoformulations induce significantly decreased immune response, resulting in excellent safety without compromising cytolytic potential. We now report the first application of D-melittin and its micellar formulations for cancer treatment. D-melittin was delivered by a pH-sensitive polymer carrier that (i) forms micellar nanoparticles at normal physiological conditions, encapsulating melittin, and (ii) dissociates at endosomal pH, restoring melittin activity. D-melittin micelles (DMM) exhibits significant cytotoxicity and induces hemolysis in a pH-dependent manner. In addition, DMM induce immunogenic cell death, revealing its potential for cancer immunotherapy. Indeed, in vivo studies demonstrated the superior safety profile of DMM over free peptide and improved efficacy at prohibiting tumor growth. Overall, we present the first application of micellar D-melittin for cancer therapy. These findings establish a new strategy for safe, systemic delivery of melittin, unlocking a potential pathway toward clinical translation for cytotoxic peptides as anti-cancer agents. which can revolutionize in vivo delivery of therapeutic peptides and peptide antigens.

Multifunctional hybrid sponge for in situ postoperative management to inhibit tumor recurrence.

Disseminated tumor cells in bleeding and residual tumor cells in the resection tumor site are the primary factors that result in tumor recurrence after surgery. Safe and efficient local implantation of the drug depot system into the resection cavity to inhibit tumor recurrence would be of great benefit to reduce the mortality of postoperative patients. Here, a sandwich-like doxorubicin-triptolide-loaded fiber/(chitosan/gelatin) sponge, DTF/CGS, is fabricated, combining hemostatic, antibacterial, and chemotherapeutic capability. The CGS obtained via freeze-drying can efficiently prevent bleeding; meanwhile, the metastatic residual tumor cells are stuck with the clotted absorbed blood. Subsequently, dual drugs released from the electrospun fiber can further kill the stuck tumor cells in CGS and the disseminated tumor cells to significantly inhibit the tumor recurrence. This antitumor recurrence strategy by immediately implanting a multifunctional hybrid sponge for in situ postoperative management may possess great potential for preventing tumor recurrence.

Design of Polymeric Carriers for Intracellular Peptide Delivery in Oncology Applications.

In recent decades, peptides, which can possess high potency, excellent selectivity, and low toxicity, have emerged as promising therapeutics for cancer applications. Combined with an improved understanding of tumor biology and immuno-oncology, peptides have demonstrated robust antitumor efficacy in preclinical tumor models. However, the translation of peptides with intracellular targets into clinical therapies has been severely hindered by limitations in their intrinsic structure, such as low systemic stability, rapid clearance, and poor membrane permeability, that impede intracellular delivery. In this Review, we summarize recent advances in polymer-mediated intracellular delivery of peptides for cancer therapy, including both therapeutic peptides and peptide antigens. We highlight strategies to engineer polymeric materials to increase peptide delivery efficiency, especially cytosolic delivery, which plays a crucial role in potentiating peptide-based therapies. Finally, we discuss future opportunities for peptides in cancer treatment, with an emphasis on the design of polymer nanocarriers for optimized peptide delivery.

Replacement of L-amino acid peptides with D-amino acid peptides mitigates anti-PEG antibody generation against polymer-peptide conjugates in mice.

The generation of anti-PEG antibodies in response to PEGylated proteins, peptides, and carriers significantly limits their clinical applicability. IgM antibodies mediate the clearance of these therapeutics upon repeat injection, resulting in toxicity and hindered therapeutic efficacy. We observed this phenomenon in our polymer platform, virus-inspired polymer for endosomal release (VIPER), which employs pH-sensitive triggered display of a lytic peptide, melittin, to facilitate endosomal escape. While the polymer-peptide conjugate was well tolerated after a single injection, we observed unexpected mortality upon repeat injection. Thus, the goal of this work was to enhance the safety and tolerability of VIPER for frequent dosing. Based on previous reports on anti-PEG antibodies and the adjuvant activity of melittin, we characterized the antibody response to polymer, peptide, and polymer-peptide conjugates after repeat-dosing and measured high IgM titers that bound PEG. By substituting the L-amino acid peptide for its D-amino acid enantiomer, we significantly attenuated the anti-PEG antibody generation and toxicity, permitting repeat-injections. We attempted to rescue mice from L-melittin induced toxicity by prophylactic injection of platelet activating factor (PAF) antagonist CV-6209, but observed minimal effect, suggesting that PAF is not the primary mediator of the observed hypersensitivity response. Overall, we demonstrated that the D-amino acid polymer-peptide conjugates, unlike L-amino acid polymer-peptide conjugates, exhibit good tolerability in vivo, even upon repeat administration, and do not elicit the generation of anti-PEG antibodies.

Unimolecular Polypeptide Micelles via Ultrafast Polymerization of N-Carboxyanhydrides.

Polypeptide micelles are widely used as biocompatible nanoplatforms but often suffer from their poor structural stability. Unimolecular polypeptide micelles can effectively address the structure instability issue, but their synthesis with uniform structure and well-controlled and desired sizes remains challenging. Herein we report the convenient preparation of spherical unimolecular micelles through dendritic polyamine-initiated ultrafast ring-opening polymerization of N-carboxyanhydrides (NCAs). Synthetic polypeptides with exceptionally high molecular weights (up to 85 MDa) and low dispersity (D < 1.05) can be readily obtained, which are the biggest synthetic polypeptides ever reported. The degree of polymerization was controlled in a vast range (25-3200), giving access to nearly monodisperse unimolecular micelles with predictable sizes. Many NCA monomers can be polymerized using this ultrafast polymerization method, which enables the incorporation of various structural and functional moieties into the unimolecular micelles. Because of the simplicity of the synthesis and superior control over the structure, the unimolecular polypeptide micelles may find applications in nanomedicine, supermolecular chemistry, and bionanotechnology.

Rationally Designed Polymer Conjugate for Tumor-Specific Amplification of Oxidative Stress and Boosting Antitumor Immunity.

The crosstalk between tumor and stroma cells is a central scenario in the tumor microenvironment (TME). While the predominant effect of tumor cells on immune cells is establishing an immunosuppressive context, tumor cell death at certain conditions will boost antitumor immunity. Herein, we report a rationally designed tumor specific enhanced oxidative stress polymer conjugate (TSEOP) for boosting antitumor immunity. The TSEOP is prepared by Passerini reaction between cinnamaldehyde (CA), 4-formylbenzeneboronic acid pinacol ester, and 5-isocyanopent-1-yne, followed by azide-alkyne click reaction with poly(l-glutamic acid)-graft-poly(ethylene glycol) monomethyl ether (PLG-g-mPEG). Under tumor stimuli condition, CA and quinone methide (QM) are quickly generated, which cooperatively induce strong oxidative stress, immunogenic tumor cell death (ICD), and activation of antigen presenting cells. In vivo studies show that the TSEOP treatment boosts tumor-specific antitumor immunity and eradicates both murine colorectal and breast tumors. This study should be inspirational for designing polymers as immunotherapeutics in cancer therapy.

Neutralizing tumor-promoting inflammation with polypeptide-dexamethasone conjugate for microenvironment modulation and colorectal cancer therapy.

Tumor is known as "a wound that does not heal". Tumor-promoting inflammation plays a crucial role in carcinogenesis, tumor progression, tumor metastasis, as well as chemotherapy resistance. Therefore, reducing tumor-promoting inflammation may be a key aspect in targeting the tumor microenvironment for cancer therapy. Dexamethasone (DEX), a commercial drug in the treatment of many different inflammatory diseases, can effectively inhibit the release of substances causing inflammation. However, as a corticosteroid medication, direct use of DEX results in many severe side effects. In this study, a redox and pH dual sensitive polypeptide-DEX conjugate (L-SS-DEX) was synthesized, and the L-SS-DEX dramatically increased the tumoral accumulation of DEX in murine colorectal cancer model (CT26) compared to free DEX. Importantly, at equal dose (10 mg/kg), L-SS-DEX showed superior antitumor activity over free DEX: 86% tumor suppression rate of L-SS-DEX treatment group compared to 49% of free DEX treatment group. Further analysis of the tumor tissues showed that cyclooxygenase-2 (COX-2) and α-smooth muscle actin (α-SMA) were significantly reduced after the L-SS-DEX treatment compared with control groups. In addition, the immunosuppressive microenvironment of the CT26 tumor was effectively relieved after L-SS-DEX treatment, characterized by increased CD8+ T cell infiltration, increased ratio of M1 over M2 macrophages, as well as markedly decrease in regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). The above results suggest that anti-inflammatory drugs hold great potential in modulating the tumor microenvironment when delivered properly, and can also result in significant tumor inhibition effects. Since dramatic amounts of anti-inflammatory drugs have been used in clinic, our results may provide improved tumor therapy options of using anti-inflammatory drugs for cancer therapy.

Co-delivery of dual chemo-drugs with precisely controlled, high drug loading polymeric micelles for synergistic anti-cancer therapy.

Simultaneous delivery of multiple chemotherapeutics using polymeric micelles often suffers from unsatisfactory drug loading, drug ratio management, and drug release. Herein, we report a feasible strategy to prepare micelles with ultra-high drug loading and a controllable drug ratio through the introduction of donor-acceptor interactions between drugs and polymeric carriers. An amphiphilic copolymer modified with phenylboronic acid moieties on the hydrophobic segment was synthesized, in which phenylboronic acid functioned as an electron acceptor and formed donor-acceptor coordination with doxorubicin (DOX) and irinotecan (IR). The obtained dual-drug-loaded micelles possessed high drug loading (up to 50%), a tunable drug ratio, and a uniform particle size. Furthermore, both of the encapsulated drug cargoes could be effectively and selectively released in cancer cells with over-produced reactive oxygen species (ROS), and thus the drug-loaded micelles exhibited synergistic anticancer efficacy and reduced systemic toxicity.

Facile synthesis of helical multiblock copolypeptides: minimal side reactions with accelerated polymerization of N-carboxyanhydrides.

Multiblock copolypeptides have attracted broad interests because their potential to form ordered structures and possess protein-mimetic functions. Controlled synthesis of multiblock copolypeptides through the sequential addition of N-carboxyanhydrides (NCAs), especially with the block number higher than five, however, is challenging and rarely reported due to competing side reactions during the polymerization process. Herein we report the unprecedented synthesis of block copolypeptides with up to 20 blocks, enabled by ultrafast polypeptide chain propagation in a water/chloroform emulsion system that outpaces side reactions and ensures high end-group fidelity. Well-defined multiblock copolypeptides with desired block numbers, block lengths, and block sequences as well as very low dispersity were readily attainable in a few hours. This method paves the way for the fast production of a large number of sequence-regulated multiblock copolypeptide materials, which may exhibit interesting assembly behaviors and biomedical applications.